Protected forms of pharmacologically active agents and uses therefor

ABSTRACT

In accordance with the present invention, there are provided conjugates of dithiocarbamates “DC”) and pharmacologically active agents (e.g., NSAIDs). Invention conjugates provide a new class of pharmacologically active agents (e.g., anti-inflammatory agents) which cause a much lower incidence of side-effects due to the protective effects imparted by modifying the pharmacologically active agents as described herein.

FIELD OF THE INVENTION

The present invention relates to novel conjugated forms ofpharmacologically active agents, and methods for the preparation and usethereof. In a particular aspect of the invention, methods are providedfor treating a pathological condition with a protected form of apharmacologically active agent, thereby reducing the occurrence ofside-effects caused thereby.

BACKGROUND OF THE INVENTION

Despite the advent of modern pharmaceutical technology, many drugs stillpossess untoward toxicities which often limit the therapeutic potentialthereof. For example, although non-steroid anti-inflammatory drugs(NSAIDs) are a class of compounds which are widely used for thetreatment of inflammation, pain and fever, NSAIDs (e.g., naproxen,aspirin, ibuprofen and ketoprofen) can cause gastrointestinal ulcers, aside-effect that remains the major limitation to the use of NSAIDs (see,for example, J. L. Wallace, in Gastroenterol. 112:1000-1016 (1997); A.H. Soll et al., in Ann Intern Med. 114:307-319 (1991); and J. Bjarnasonet al., in Gastroenterol. 104:1832-1847 (1993)).

There are two major ulcerogenic effects of NSAIDs: (1) topical irritanteffects on the epithelium of the gastrointestinal tract and (2)suppression of gastrointestinal prostaglandin synthesis. In recentyears, numerous strategies have been attempted to design and develop newNSAIDs that reduce the damage to the gastrointestinal tract. Theseefforts, however, have largely been unsuccessful. For example, entericcoating or slow-release formulations designed to reduce the topicalirritant properties of NSAIDs have been shown to be ineffective in termsof reducing the incidence of clinically significant side effects,including perforation and bleeding (see, for example, D. Y. Graham etal., in Clin. Pharmacol. Ther. 38:65-70 (1985); and J. L. Carson, etal., in Arch. Intern. Med., 147:1054-1059 (1987)).

As another strategy to address the potential for NSAIDs to produceclinically significant side effects, Medford et al. (see, for example,PCT Publication No. WO 95/30415 and U.S. Pat. No. 5,807,884) haveproposed preparation of drug derivatives of dithiocarbomates having thestructure:

A—S—C(S)—B,

wherein B represents the drug moiety. This specific structure isrequired because a goal of Medford's work is to maintain theaccessability of the —C(S)—S— moiety as a reactive species.

It is well recognized that aspirin and other NSAIDs exert theirpharmacological effects through the inhibition of cyclooxygenase (COX)enzymes, thereby blocking prostaglandin synthesis (see, for example, J.R. Van in Nature, 231:232-235 (1971)). There are two types of COXenzymes, namely COX-1 and COX-2. COX-1 is expressed constitutively inmany tissues, including the stomach, kidney, and platelets, whereasCOX-2 is expressed only at the site of inflammation (see, for example,S. Kargan et al. in Gastroenterol., 111:445-454 (1996)). Theprostagladins derived from COX-1 are responsible for many of thephysiological effects, including maintenance of gastric mucosalintegrity.

Many attempts have been made to develop NSAIDs that only inhibit COX-2,without impacting the activity of COX-1 (see, for example, J. A.Mitchell et al., in Proc. Natl. Acad. Sci. USA 90:11693-11697 (1993);and E. A. Meade et al., in J. Biol. Chem., 268:6610-6614 (1993)). Thereare at least two NSAIDs presently on the market (i.e., nabumetone andetodolac) that show marked selectivity for COX-2 (see, for example, E.A. Meade, supra.; and K. Glaser et al., in Eur. J. Pharmacol.281:107-111 (1995)). These drugs appear to have reduced gastrointestinaltoxicity relative to other NSAIDs on the market.

On the basis of encouraging clinical as well as experimental data, thedevelopment of highly selective COX-2 inhibitors appears to be a soundstrategy to develop a new generation of anti-inflammatory drugs.However, the physiological functions of COX-1 and COX-2 are not alwayswell defined. Thus, there is a possibility that prostagladins producedas a result of COX-1 expression may also contribute to inflammation,pain and fever. On the other hand, prostagladins produced by COX-2 havebeen shown to play important physiological functions, including theinitiation and maintenance of labor and in the regulation of boneresorption (see, for example, D. M. Slater et al., in Am. J. Obstet.Gynecol., 172:77-82 (1995); and Y. Onoe et al., in J. Immunol.156:758-764 (1996)), thus inhibition of this pathway may not always bebeneficial. Considering these points, highly selective COX-2 inhibitorsmay produce additional side effects above and beyond those observed withstandard NSAIDs, therefore such inhibitors may not be highly desirable.

Accordingly, there is still a need in the art for modified forms ofNSAIDs, and other pharmacologically active agents, which cause a reducedincidence of side-effects, relative to the incidence of side-effectscaused by such pharmacologically active agents as aspirin, ibuprofen,and the like.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided conjugatesof physiologically compatible dithiocarbamates (DC) andpharmacologically active agents (e.g., NSAIDs). Invention conjugates(e.g., DC-NSAIDs) provide a new class of pharmacologically active agents(e.g., anti-inflammatory agents) which cause a much lower incidence ofside-effects due to the protective effects imparted by modifying thepharmacologically active agents as described herein.

There are a number of advantages of conjugates according to theinvention (e.g., DC-NSAID), including:

(i) reduced topical irritant effects of NSAIDs, and

(ii) enhanced tissue delivery of both drugs as a result of a decrease innet charges on the molecule, particularly for acidic NSAIDs such asnaproxen, aspirin, diclofenac and ibuprofen, thereby reducing thequantity of material which must be delivered to achieve an effectivedosage.

In accordance with the present invention, cleavage of the novelbio-cleavable conjugates described herein releases the activepharmaceutical agent. In contrast to the prior art, however (see, forexample, Medford et al., referred to above), no free dithiocarbamate isreleased upon such cleavage. In the event the dithiocarbamate linkage iscleaved, a thiocarbonylcarboxy moiety (—C(S)—O—) will be generatedinstead of the dithiocarbonyl moiety (—C(S)—S—) required for adithiocarbamate functionality. Thus, the means selected for linkage of apharmacologically active agent to a dithiocarbamate has a dramaticeffect on the species released in situ.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the improved gastric safety of a Naproxen prodrugaccording to the invention (relative to unmodified Naproxen) in a ratmodel. The number of gastric lesions was measured three hours after oraldosing of fasted male Sprague-Dawley rats with vehicle, 2 differentdoses of naproxen or 2 different doses of a molar equivalent of Naproxenprodrug.

FIG. 2 illustrates the alleviation of acute inflammation by Naproxenprodrug according to the invention in a carrageenen model in rats. Pawvolume increases (measured with a Plethysmometer) are reported as afunction of time, and were measured on the injected feet of maleSprague-Dawley rats which had been pretreated at −1 hour with oralvehicle, naproxen or Naproxen prodrug, then injected transderrnally with1% carrageenen. Blackened boxes represent untreated animals, checkeredboxes represent animals to whom vehicle (5% DMSO/CMC) was administered,open boxes represent naproxen administration at 3 mg/kg, verticallylined boxes represent naproxen administration at 10 mg/kg, horizontallylined boxes represent Naproxen prodrug administration at 5.5 mg/kg(molar equivalent of 3 mg/kg naproxen alone), and diagonallycross-hatched boxes represent Naproxen prodrug/kg (molar equivalent of10 mg/kg naproxen alone).

FIG. 3 illustrates the effectiveness of Naproxen prodrug according tothe invention in the treatment of adjuvant-induced arthritis in a ratmodel system. Thus, paw volume increases (measured with aPlethysmometer) are reported as a function of time, and were measured inthe injected feet of Lewis male rats in which arthritis was induced byintradermal injection of adjuvant into the footpad. Rats were injectedon day 0 and treated once orally with either vehicle, naproxen orNaproxen prodrug on days 5-8 and 11-14. Blackened boxes representanimals treated with vehicle (5% DMSO/CMC); checkered boxes representanimals treated with naproxen at 1 mg/kg, open boxes represent animalstreated with naproxen at 10 mg/kg, vertically lined boxes representanimals treated with Naproxen prodrug at 1.8 mg/kg (molar equivalent of1 mg/kg naproxen alone), and horizontally lined boxes represent animalstreated with Naproxen prodrug, at 18 mg/kg (molar equivalent of 10 mg/kgnaproxen alone).

FIG. 4 presents concentration versus time curves for naproxen followingIV administration of naproxen or Naproxen prodrug according to theinvention. Blackened rectangles represent plasma concentration ofnaproxen following IV administration of 0.55 mg/kg of naproxen and opentriangles represent plasma concentration of naproxen following IVadministration of 1.1 mg/kg of Naproxen prodrug. After IV administrationof naproxen, the naproxen plasma concentrations declined in abi-exponential manner. The decline of plasma naproxen following Naproxenprodrug administration was monophonic. Note the lower plasma C_(max)shown for Naproxen prodrug.

FIG. 5 presents concentration versus time curves for naproxen followingoral administration of naproxen or Naproxen prodrug according to theinvention. Open triangles represent plasma concentration of naproxenfollowing oral administration of 2.2 mg/kg of naproxen and blackenedrectangles represent plasma concentration of naproxen following oraladministration of 4 mg/kg of Naproxen prodrug. Following oraladministration of Naproxen prodrug, the time to maximum concentration ofnaproxen in plasma was considerably longer compared to naproxenadministration (T_(max) of 6.4 and 1.3 hours for Naproxen prodrug andnaproxen, respectively). The corresponding C_(max) values were 2.34 and4.82 μg/mL for Naproxen prodrug and naproxen, respectively. There was nosignificant difference for AUC_(nif) values.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided compoundscomprising dithiocarbamate covalently attached to a pharmacologicallyactive agent. Invention compounds comprise chemically modifiedpharmacologically active agents having the structure:

Z—C(S)—S—L—Q

wherein:

Q=a pharmacologically active agent,

L=a linker/spacer, and

Z=a modifying group.

Invention compounds can be readily prepared in a variety of ways, e.g.,by reaction of dithiocarbamates with pharmacologically active agentsemploying a suitable linker/spacer.

Dithiocarbamates are sulfur-containing small molecules that are knownheavy metal chelators (see, for example, F. W. Sunderman, in Ann. Clin.Lab. Sci., 8:259-69 (1978); and M. M. Jones and M. G. Cherian, inToxicology, 62:1-25 (1990)). Dithiocarbamates such asdiethyl-dithiocarbarnate have been used clinically in the treatment ofnickel poisoning (see, for example, Sunderman, supra) and were used inclinical trials for the treatment of AIDS patients (see, for example, E.Reisinger et al., in Lancet, 335:679 (1990)).

Dithiocarbamates such as pyrrolidine dithiocarbamate are potentinhibitors of nuclear factor kappa B in intact cells (see, for example,R. Schreck et al., in J. Exp. Med., 175:1181-1194 (1992)). In addition,nuclear factor kappa B has been shown to up-regulate the expression ofcell adhesive molecules, including the vascular cell adhesive molecule 1(VCAM-1; see, for example, M. F. Iademarco et al., in J. Biol. Chem.,267:16323-16329 (1992)). Endothelial expression of VCAM-1 causes theadherence of neutrophils to the endothelium, an early event leading toinflammation and subsequent vascular damage and reduction of blood flow(see, for example, M. N. Oppenheimer et al., in J. Immunol.,147:42207-4210 (1991)). It has been recognized that NSAID administrationincreases neutrophil adherence to the vascular endothelium in thegastric and mesenteric microcirculation (see, for example, J. L. Wallaceet al., in Gastroenterol., 105:1630-1636 (1993); and H. Asako et al., inAm J. Physiol., 262:G903-G908 (1992)). Therefore, conjugates of NSAIDswith dithiocarbamate would block VCAM-1 expression, thereby avoiding thevascular problems associated with neutrophil adherence to theendothelium.

Suitable dithiocarbamate compounds contemplated for use in the practiceof the present invention can be described with reference to genericstructure I as follows:

[R₁R₂N—C(S)—S⁻]_(x)M^(+1,+2,+3)  (I)

wherein:

each of R₁ and R₂ is independently selected from a C₁ up to C₁₈ alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic,substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substitutedarylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl,substituted arylalkynyl, aroyl, substituted aroyl, acyl, substitutedacyl, or

R₁ and R₂ cooperate to form a 5-, 6- or 7-membered ring including N, R₁and R₂, or

R₁ or R₂ is a divalent moiety selected from the group consisting ofalkylene, substituted alkylene, cycloalkylene, substitutedcycloalkylene, heterocyclic, substituted heterocyclic, oxyalkylene,substituted oxyalkylene, alkenylene, substituted alkenylene, arylene,substituted arylene, alkarylene, substituted alkarylene, aralkylene andsubstituted aralkylene, wherein said divalent moiety serves as the samesubstituent for two dithiocarbamate structures, thereby linking saidstructures together so as to form a bis(dithiocarbamate) species,

x is 1 or 2, and

M is a monovalent cation when x is 1, or M is a physiologicallycompatible divalent or trivalent transition metal cation when x is 2.

Presently preferred dithiocarbamate compounds having generic structure Iare those wherein:

each of R₁ and R₂=a C₁ up to C₁₂ alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl or substituted alkynyl, wherein thesubstituents are selected from carboxyl, —C(O)H, oxyacyl, phenol,phenoxy, pyridinyl, pyrrolidinyl, amino, amido, hydroxy, nitro orsulfuryl, or

R₁ and R₂ cooperate to form a 5-, 6- or 7-membered ring including N, R₁and R₂, and

M=Na⁺ or NH⁺ ₄.

Especially preferred dithiocarbamate compounds having generic structureI are those wherein:

R₁ is selected from a C₂ up to C₈ alkyl or substituted alkyl, whereinthe substituents are selected from carboxyl, acetyl, pyridinyl,pyrrolidinyl, amino, amido, hydroxy or nitro, and

R₂ is selected from a C_(1 up to C) ₆ alkyl or substituted alkyl, or

R₂ cooperates with R₁ to form a 5-, 6- or 7-membered ring including N,R₂ and R₁, and

M=Na⁺ or NH⁺ ₄.

The presently most preferred dithiocarbamate compounds having genericstructure I are those wherein:

R₁ is selected from a C₂ up to C₈ alkyl or substituted alkyl, whereinthe substituents are selected from carboxyl, acetyl, amido or hydroxy,and

R₂ is selected from a C₁ up to C₄ alkyl or substituted alkyl, or

R₂ cooperates with R₁ to form a 5- or 6-membered ring including N, R₂and R₁, and

M=Na⁺ or NH⁺ ₄.

When R₁ and R₂ cooperate to form a 5-, 6- or 7-membered ring, thecombination of R₁ and R₂ can be a variety of saturated or unsaturated 4,5 or 6 atom bridging species selected from alkenylene or —O—, —S—,—C(O)—and/or —N(R)-containing alkylene moieties, wherein R is hydrogen or alower alkyl moiety. Presently preferred dithiocarbamates wherein R₁ andR₂ cooperate to form a ring structure include pyrrolidinedithiocarbamate, proline dithiocarbamate, pyridine dithiocarbamate,pyridinium dithiocarbamate, pyrimidine dithiocarbamate, pyrrolinedithiocarbamate, and the like.

Examples of presently preferred dithiocarbamates contemplated for useherein for the preparation of invention conjugates include sarcosinedithiocarbamate, iminodiacetic acid dithiocarbamate,diethyldithiocarbamate, diisopropyldithiocarbamate, sugar-linkeddithiocarbamates (e.g., glucose-, lactose-, mannose-, fructose-linkeddithiocarbamates, and the like), pyrrolidine dithiocarbamate, prolinedithiocarbamate, and the like.

Monovalent cations contemplated for incorporation into theabove-described dithiocarbamate compounds include Na⁺, NH₄ ⁺, tetraalkylammonium, and the like. Physiologically compatible divalent or trivalenttransition metal cations contemplated for incorporation into theabove-described dithiocarbamate compounds include charged forms of iron,cobalt, copper, manganese, ruthenium, or the like (e.g., Fe⁺², Fe⁺³,Co⁺², Co⁺³, Cu⁺², Mn⁺², Mn⁺³ or Ru⁺³). In accordance invention, theratio of dithiocarbamate-species to counter-ion M can vary widely. Thus,dithiocarbamate-containing nitric oxide scavenger can be administeredwithout any added metallic counter-ion (i.e., M=H⁺, or a transitionmetal cation to dithiocarbamate-species ratio of zero), with ratios oftransition metal cation to dithiocarbamate-species up to about 1:2(i.e., a 2:1 ratio of dithiocarbamate:transition metal cation) beingsuitable.

As employed herein, “substituted alkyl” comprises alkyl groups furtherbearing one or more substituents selected from hydroxy, alkoxy (of alower alkyl group), mercapto (of a lower alkyl group), cycloalkyl,substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl,substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, halogen, trifluoromethyl, cyano, nitro, nitrone,amino, amido, —C(O)H, acyl, oxyacyl, carboxyl, carbamate, sulfonyl,sulfonamide, sulfuryl, and the like.

As employed herein, “cycloalkyl” refers to cyclic ring-containing groupscontaining in the range of about 3 up to 8 carbon atoms, and“substituted cycloalkyl” refers to cycloalkyl groups further bearing oneor more substituents as set forth above.

As employed herein, “alkenyl” refers to straight or branched chainhydrocarbyl groups having at least one carbon-carbon double bond, andhaving in the range of about 2 up to 12 carbon atoms, and “substitutedalkenyl” refers to alkenyl groups further bearing one or moresubstituents as set forth above.

As employed herein, “alkynyl” refers to straight or branched chainhydrocarbyl groups having at least one carbon-carbon triple bond, andhaving in the range of about 2 up to 12 carbon atoms, and “substitutedalkynyl” refers to alkynyl groups further bearing one or moresubstituents as set forth above.

As employed herein, “aryl” refers to aromatic groups having in the rangeof 6 up to 14 carbon atoms and “substituted aryl” refers to aryl groupsfurther bearing one or more substituents as set forth above.

As employed herein, “alkylaryl” refers to alkyl-substituted aryl groupsand “substituted alkylaryl” refers to alkylaryl groups further bearingone or more substituents as set forth above.

As employed herein, “arylalkyl” refers to aryl-substituted alkyl groupsand “substituted arylalkyl” refers to arylalkyl groups further bearingone or more substituents as set forth above.

As employed herein, “arylalkenyl” refers to aryl-substituted alkenylgroups and “substituted arylalkenyl” refers to arylalkenyl groupsfurther bearing one or more substituents as set forth above.

As employed herein, “arylalkynyl” refers to aryl-substituted alkynylgroups and “substituted arylalkynyl” refers to arylalkynyl groupsfurther bearing one or more substituents as set forth above.

As employed herein, “aroyl” refers to aryl-carbonyl species such asbenzoyl and “substituted aroyl” refers to aroyl groups further bearingone or more substituents as set forth above.

As employed herein, “heterocyclic” refers to cyclic (i.e.,ring-containing) groups containing one or more heteroatoms (e.g., N, O,S, or the like) as part of the ring structure, and having in the rangeof 3 up to 14 carbon atoms and “substituted heterocyclic” refers toheterocyclic groups further bearing one or more substituents as setforth above.

As employed herein, “acyl” refers to alkyl-carbonyl species.

As employed herein, “halogen” refers to fluoride, chloride, bromide oriodide atoms.

Diseases and conditions contemplated for treatment in accordance withthe present invention include inflammatory and infectious diseases, suchas, for example, septic shock, hemorrhagic shock, anaphylactic shock,toxic shock syndrome, ischemia, cerebral ischemia, administration ofcytokines, overexpression of cytokines, ulcers, inflammatory boweldisease (e.g., ulcerative colitis or Crohn s disease), diabetes,arthritis, asthma, Alzheimer s disease, Parkinson s disease, multiplesclerosis, cirrhosis, allograft rejection, encephalomyelitis,meningitis, pancreatitis, peritonitis, vasculitis, lymphocyticchoriomeningitis, glomerulonephritis, uveitis, ileitis, inflammation(e.g., liver inflammation, renal inflammation, and the like), burn,infection (including bacterial, viral, fungal and parasitic infections),hemodialysis, chronic fatigue syndrome, stroke, cancers (e.g., breast,melanoma, carcinoma, and the like), cardiopulmonary bypass,ischemic/reperfusion injury, gastritis, adult respiratory distresssyndrome, cachexia, myocarditis, autoimmune disorders, eczema,psoriasis, heart failure, heart disease, atherosclerosis, dermatitis,urticaria, systemic lupus erythematosus, AIDA, AIDS dementia, chronicneurodegenerative disease, chronic pain, priapism, cystic fibrosis,amyotrophic lateral sclerosis, schizophrenia, depression, premenstrualsyndrome, anxiety, addiction, migraine, Huntington s disease, epilepsy,neurodegenerative disorders, gastrointestinal motility disorders,obesity, hyperphagia, solid tumors (e.g., neuroblastoma), malaria,hematologic cancers, myelofibrosis, lung injury, graft-versus-hostdisease, head injury, CNS trauma, hepatitis, renal failure, liverdisease (e.g., chronic hepatitis C), drug-induced lung injury (e.g.,paraquat), myasthenia gravis (MG), ophthalmic diseases,post-angioplasty, restenosis, angina, coronary artery disease, and thelike.

Pharmacologically active agents contemplated for modification inaccordance with the present invention include:

NSAIDs, such as acetaminophen (Tylenol, Datril, etc.), aspirin,ibuprofen (Motrin, Advil, Rufen, others), choline magnesium salicylate(Triasate), choline salicylate (Anthropan), diclofenac (voltaren,cataflam), diflunisal (dolobid), etodolac (lodine), fenoprofen calcium(nalfon), flurobiprofen (ansaid), indomethacin (indocin, indometh,others), ketoprofen (orudis, oruvail), ketorolac tromethamine (toradol),magnesium salicylate (Doan s, magan, mobidin, others), meclofenamatesodium (meclomen), mefenarnic acid (relafan), oxaprozin (daypro),piroxicam (feldene), sodium salicylate, sulindac (clinoril), tolmetin(tolectin), meloxicam, nabumetone, naproxen, lornoxicam, nimesulide,indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide, and thelike;

analgesics/antipyretics (e.g., aspirin, acetaminophen, ibuprofen,naproxen sodium, buprenorphine hydrochloride, propoxyphenehydrochloride, propoxyphene napsylate, meperidine hydrochloride,hydromorphone hydrochloride, morphine sulfate, oxycodone hydrochloride,codeine phosphate, dihydrocodeine bitartrate, pentazocine hydrochloride,hydrocodone bitartrate, levorphanol tartrate, diflunisal, trolaminesalicylate, nalbuphine hydrochloride, mefenamic acid, butorphanoltartrate, choline salicylate, butalbital, phenyltoloxamine citrate,diphenhydramine citrate, methotrimeprazine, cinnamedrine hydrochloride,meprobamate, and the like);

sedatives/hypnotics (e.g., barbiturates (e.g., pentobarbital,pentobarbital sodium, secobarbital sodium), benzodiazapines (e.g.,flurazepam hydrochloride, triazolam, tomazeparm, midazolamhydrochloride, and the like);

antianginal agents (e.g., beta-adrenergic blockers, calcium channelblockers (e.g., nifedipine, diltiazem hydrochloride, and the like),nitrates (e.g., nitroglycerin, isosorbide dinitrate, pentaerythritoltetranitrate, erythrityl tetranitrate, and the like));

antianxiety agents (e.g., lorazepam, buspirone hydrochloride, prazepam,chlordiazepoxide hydrochloride, oxazeparn, clorazepate dipotassium,diazepam, hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam,droperidol, halazepam, chlormezanone, and the like);

antidepressants (e.g., doxepin hydrochloride, amoxapine, trazodonehydrochloride, amitriptyline hydrochloride, maprotiline hydrochloride,phenelzine sulfate, desipramine hydrochloride, nortriptylinehydrochloride, tranylcyprornine sulfate, fluoxetine hydrochloride,doxepin hydrochloride, imipramine hydrochloride, imipramine pamoate,nortriptyline, amitriptyline hydrochloride, isocarboxazid, desipraminehydrochloride, trimipramine maleate, protriptyline hydrochloride, andthe like);

antipsychotic agents (e.g., haloperidol, loxapine succinate, loxapinehydrochloride, thioridazine, thioridazine hydrochloride, thiothixene,fluphenazine hydrochloride, fluphenazine decanoate, fluphenazineenanthate, trifluoperazine hydrochloride, chlorpromazine hydrochloride,perphenazine, lithium citrate, prochlorperazine, and the like);

antimanic agents (e.g., lithium carbonate),

antiarrhythmics (e.g., bretylium tosylate, esmolol hydrochloride,verapamil hydrochloride, amiodarone, encainide hydrochloride, digoxin,digitoxin, mexiletine hydrochloride, disopyramide phosphate,procainamide hydrochloride, quinidine sulfate, quinidine gluconate,quinidine polygalacturonate, flecainide acetate, tocainidehydrochloride, lidocaine hydrochloride, and the like);

antihypertensive drugs, such as diuretics (hydrochlorothiazide,chlorthalidone, metolazone, indapamide, furosemide, bumetanide,torsemide, triamterene, amiloride, spronolactone), beta-adrenergicblocking agents (acebutolol, atenolol, betaxolol, cartelol, labetalol,metoprolol, nadolol, penbutolol, pindolol, propranolol, timolol),angiotensin converting enzyme inhibitors (benazepril, captopril,enalapril, fosinopril, quinoapril, ramimpril, losartan), calciumchannel-blocking agents (diltiazem, verapamil, amlodipine, felodipine,isradipine, nicardipine, nifedipine), aplha-adrenoceptor blockingagents, sympatholytics, and vasodilators (such as prazosin, terazosin,doxazosin, clonidine, guanabenz, guanfacine, methylodopa, guanethidine,guanethidine monosulfate, reserpine, hydralazine, minoxidil, and thelike), as well as agents such as trimethaphan camsylate,phenoxybenzamine hydrochloride, pargyline hydrochloride, deserpidine,diazoxide, rescinnamine, sodium nitroprusside, rauwolfia serpentina,alseroxylon, phentolamine mesylate, and the like;

antihistamine/antipruritic drugs, such as ethanolamines (e.g.,diphenhydramine, diphenhydramine hydrochloride, clemastine, clemastinefumarate, and the like), ethylenediamines (e.g., brompheniramine,brompheniramine maleate, chlorpheniramine, chlorpheniramine maleate,dexchlorpheniramine maleate, triprolidine, triprolidine hydrochloride,and the like), phenothiazines (e.g., promethazine), piperidines (e.g.,hydroxzine, hydroxyzine hydrochloride, terfenadine, astemizole,azatadine, azatadine maleate, and the like), cyproheptadine,cyproheptadine hydrochloride, loratidine, carbinoxamine maleate,diphenylpyraline hydrochloride, phenindamine tartrate, tripelennaminehydrochloride, methdilazine hydrochloride, trimprazine tartrate, and thelike;

immunosuppressants, such as glucocorticoids (methylprednisolone), myelinbasic protein (e.g., 7-capaxone), anti-Fc receptor monoclonalantibodies, hydroorotate dehydrogenase inhibitor, anti-IL2 monoclonalantibodies (e.g., CHI-621 and dacliximab), buspirone, castanospermine,CD-59 (complement factor inhibitor), 5-lipoxygenase inhibitor (e.g.,CMI-392), phosphatidic acid synthesis antagonists, ebselen, edelfosine,enlimomab, galaptin, platelet activating factor antagonists, selectinantagonists (e.g., ICAM-4), interleukin-10 agonist, macrocylic lactone,methoxatone, mizoribine, OX-19, peptigen agents, PG-27, protein kinase Cinhibitors, phosphodiesterase IV inhibitor, single chain antigen bindingproteins, complement factor inhibitor, sialophorin, sirolimus,spirocyclic lactams, 5-hydroxytryptamine antagonist, anti-TCR monoclonalantibodies, CD5 gelonin and TOK-8801, and the like;

antimetabolite cytotoxics (azathioprine, cyclophosphamide), C5a releaseinhibitor, benzydamine, peldesine, pentostatin, SDZ-ASM-981,thalidomide, benzoporphyrin derivatives, arachidonate antagonists (e.g.,halometasone, halobetasol propionate), corticosteriod (clobetasolpropionate), growth hormone antagonists (octapeptide somatostatinanalogue, lanreotide, angiopeptin and dermopeptin), thymopentin, and thelike;

neuroprotective agents, such as α-adrenoreceptor antagonist (i.e,α-dihydroergocryptine), NMDA antagonists (e.g., 5,6,7-tichloro-THQTQ,remacemide, 2-piperazinecarboxylic acid, N-indologlycinamidederivatives, spiro[benzo(b)thiophen-4(5H) derivatives, CP-101606,eliprodil, dexanabinol, GV-150526, L-695902, L-701324, amantadinederivatives, dizocilpine, benzomorphan derivatives, aptiganel,(S)-α-phenyl-2-pyridine ethanamide dihyrochloride and1-amino-cyclopentanecarboxylic acid), sodium channel antagonists (e.g.,619C89), glycine antagonists (e.g., glystasins), calcium channelantagonists (e.g., 3,5-pyridinedicarboxylic acid derivatives,conopeptides, 1-piperazineethanol, thieno[2,3-b]pyridine-5-carboxylicacid derivatives, NS-3034, nilvadipine, nisoldipine, tirilazad mesylate,2H-1-enzopyran-6-ol, nitrone spin traps, iacidipine, iomeerzinehydrochloride, lemildipine, lifarizine, CPC-304, efonidipine, F-0401,piperazine derivatives), calpain inhibitors, fibrinogen antagonists(e.g., ancrod), integrin antagonists (e.g., antegren), thromboxane A₂antagonist (e.g., 9H-carbazole-9-propanoic acid derivatives, 5-Heptenoicacid derivatives and 1-azulenesulfonic acid derivatives), brain-derivedneurotropic factor, adrenergic transmitter uptake inhibitor (e.g.,1-butanamine), endothelin A receptor antagonists (e.g.,benzenesulfonamide derivatives, GABA A receptor antagonists (e.g.,triazolopyrimidine derivatives and cyclohexaneacetic acid derivatives),GPIIb IIIa receptor antagonists (e.g., C68-22), platelet aggregationantagonist (e.g., 2(1H)-quinolinone derivatives, 1H-pyrrole-1-aceticacid derivatives and counadin), Factor Xa inhibitor, CPC-211,corticotropin releasing factor agonist, thrombin inhibitor (e.g.,cothrombins, fraxiparine, dermatan sulfate and heparinoid), dotarizine,intracellular calcium chelators (e.g., BAPTA derivatives), radicalformation antagonists (EPC-K1, 3-pyridinecarboxamide derivatives,superoxide dismutase, raxofelast, lubeluzole, 3H-pyrazol-3-onederivatives, kynurenic acid derivatives, homopiperazine derivatives, andpolynitroxyl albumin), protein kinase inhibitors (e.g.,1H-1,4-diazepine), nerve growth agonist (e.g., floor plate factor-5),glutamate antagonist (e.g., cyclohexanepropanoic acid, riluzole, NS-409and acetamide derivatives), lipid peroxidase inhibitor (e.g.,2,5-cyclohexadiene-1,4-dione derivatives), sigma receptor agonist (e.g.,cyclopropanemethanamine derivatives and SA-4503), thyrotropin releasinghormone agonist (e.g., JTP-2942, L-prolinanide and posatirelin), prolylendopeptidase inhibitor, monosialoganglioside GM1, proteolytic enzymeinhibitor (e.g., nafamostat), neutrophil inhibitory factor, plateletactivating factor antagonist (e.g., nupafant), monoamine oxidase Binhibitor (e.g., parafluoroselegiline and benzonitrile derivatives),PARS inhibitors, Angiotensin I converting enzyme inhibitor (e.g.,perindopril and ramipril), acetylcholine agonist (e.g., pramiracetam),protein systhesis antagonist (e.g., procysteine), phosphodiesteraseinhibitor (e.g., propentofylline), opioid kappa receptor agonist (e.g.,10H-phenothiazine-2-carboxamine derivatives), complement factorinhibitor (sCRI fragments), somatomedin-1, carnitine acetyltransferasestimulant (e.g., acetylcarnitine), and the like;

T cell inhibitors such as synthetic leucocyte antigen derived peptides,interleukin-1 receptor antagonist, MG/AnergiX, anti-CD3 monoclonalantibodies, anti-CD23 monoclonal antibodies, anti-CD28 antibodies,anti-CD2 monoclonal antibodies, CD4 antagonists, anti-E selectinantibodies, MHC inhibitors, monogens, mycophenolate mofetil, LRA-1inhibitors, selectin inhibitors, and the like;

antimigraine agents, such as MK-462, 324C91, Phytomedicine,(S)-fluoxetine, calcium channel antagonists (e.g., nimodipine/Nimotop,flunarizine, dotarizine/FI-6026, iomerizine HCL/KB-2796, CPC-304, andCPC-317), α-dihydroergocryptine, 5-HT1 agonists, (e.g.,Sumatriptan/Imitrex, Imigran, GR-85548, 311C, and GR-127607), 5-HT1Dagonists, 5-HT1A antagonists, 5-HT1B antagonists (e.g., CP-93129),5-HT1D antagonists (e.g., 1H-indole-5-ethanesulfonamide derivatvies and1H-indole-5-methanesulfonamide), 5-HT1D receptor cloned (e.g., 5-HT1Dagents), 2-thiophenecarboxamide, 3-piperidinamine, diclofenac potassium,dihydroergotamine (e.g., DHE 45®), ergotamine tartrate, dolasetronmesilate, dotarizine, flupirtine, histamine-H3 receptor agonist,indobufen, 1-azulenesulfonic acid derivatives, cholinesteraseinhibitors, (e.g., S-9977), bradykinin antagonists, nitric oxidereductase inhibitors (e.g., BN-52296), nitric oxide receptorantagonists, substance P antagonists (e.g., Capsaicin/Nasocap),endopeptidase inhibitors (e.g., neutral endopeptidase, cloned),piperazine derivatives, neurokinin 1 antagonists, metergoline, dopamineD2 antagonist (e.g., metoclopramide+lysine acetyl), enkephalinaseinhibitors (e.g., neutral endopeptidase), 5-HT2 antagonists (e.g.,LY-053857), 5-HT3 antagonists (e.g., Dolasetron mesilate/MDL-73147, and4H-carbazol-4-one derivatives), tenosal, tolfenarnic acid,cyclooxygenase inhibitors (e.g., carbasalate/carbaspirin calcium, andtenosal/MR-Y134), alpha adrenoreceptor antagonists (e.g., arotinolol,and dihydroergocryptine), opioid agonists (e.g., flupirtine/D-9998),beta adrenergic antagonists (e.g., propranolol), valproate semisodium,propanolol hydrochloride, isometheptene mucate, dichloralphenazone, andthe like;

antiarthritic agents, such as anti-CD4 monoclonal antibodies,phospholipase A1 inhibitor, loteprednol, tobramycin, combinations ofloteprednol and tobramycin, salnacedin, amiprilose, anakinra, anergiX,anti-B7 antibody, anti-CD3H, anti-gp39, anti-MHC MAbs, antirheumaticpeptides, anti-Tac(Fv)-PE40, AP-1 inhibitors, AR-324, purine nucleotidephosphorylase inhibitors (e.g., BCX-5), bindarit, CD2 antagonist (e.g.,BTI-322), campath-1H, CD4 antagonist (e.g., CE9.1 and SB-210396), tumornecrosis factor antagonist (e.g., p80 TNFR, rhTNFbp, peptide T, CenTNF,thalidomide, CDP-571 and TBP-1), cobra venom factor, interleukin 1aagonist (e.g., cytogenin), interleukin 2 receptor antagonist (e.g.,dacliximab), ICAM 1 antagonist (e.g., enlimomab), interleukin 1 betaconverting enzyme inhibitors (e.g., ICE-inhibitors), interferons (e.g.,thymocartin), interleukin-10, interleukin-13, interleukin 1 antagonist(e.g., SR-31747 and TJ-114), interleukin-2 antagonist (e.g., sirolimus),phospholipase C inhibitor, neurokinin 1 antagonist (e.g., L-733060),laflunimus, leflunomide, leucotriene antagonists, levamisole, LFA3TIP,macrocyclic lactone, MHC class II inhibitors, mizoribine, mycophenolatemofetil, NfkB inhibitors, oncolysin CD6, peldesine, pidotimod, PKC-RACKinhibitors, PNP inhibitors, reumacon, CD28 antagonist, roquinimex,RWJ-50271, subreum, T7 vector, tacrolimus, VLA antagonist (e.g.,TBC-772), transforming growth factor beta agonist, methionine synthaseinhibitors (e.g., vitamin B12 antagonist), adenosine A2 receptor agonist(e.g., YT-146), CD5 antagonist (e.g., zolimomab), 5-lipoxygenaseinhibitor (e.g., zileuton, tenidap, and ABT-761), cyclooxygenaseinhibitor (e.g., tenoxicam, talmetacin, piroxicam, piroxicam cinnamate,oxaprozin, NXTHIO, ML-3000, mofezolac, nabumetone, flurbiprofen,aceclofenac, diclofenac, and dexibuprofen), metalloproteinase inhibitor(e.g., XR-168, TNF convertase inhibitors, GI-155704A, AG-3340 andBB-2983), nitric oxide synthase inhbitors (i.e, ARL-16556),phospholipase A2 inhibitor (e.g., ARL-67974), selectin antagonist (e.g.,CAM inhibitors), leucotriene B4 antagonist (e.g., CGS-25019C),collagenase inhibitor (e.g., GR-129574A), cyclooxygenase 2 inhibitor(e.g., meloxicam), thromboxane synthase inhibitor (e.g., curcumin),cysteine protease inhibitor (e.g., GR-373), metalloproteinase inhibitor(D-5410), lipocortins synthesis agonist (e.g., rimexolone, predonisolone21-farnesylate, HYC-141, and deflazacort), chelating agent (diacerein),elastase inhibitors, DNA directed RNA polymerase inhibitor (e.g.,estrogens), oxygen radical formation antagonist (e.g., glucosaminesulfate), thrombin inhibitors (e.g., GS-522), collagen inhibitors (e.g.,halofuguinone), hyaluronic acid agonist (e.g., NRD-101, hylan, Dispasan,and Hyalart), nitric oxide antagonists (e.g., hydroxocobalamin),stromelysin inhibitors (e.g., L-758354), prostaglandin E1 agonist (e.g.,misoprostol, and misoprostol+diclofenac), dihydrofolate reductaseinhibitor (e.g., trimetrexate, and MX-68), opioid antagonist (e.g.,nalmefene), corticotropin releasing factor antagonist (e.g., NBI-103,and NBI-104), proteolytic enzyme inhibitor (e.g., protease nexin-1, andNCY-2010), bradykinin antagonist (e.g., tachykinin antagonists, andNPC-17731), growth hormone antagonist (e.g., octreotide),phosphodiesterase IV inhibitor (e.g., PDEIV inhibitors), gelatinaseinhibitor (e.g., REGA-3G12), free radical scavengers (e.g., SIDR-1026),prostaglandin synthase inhibitors (e.g., sulfasalazine), phenylbutazone,penicillamine, salsalate, azathioprine, indomethacin, meclofenamatesodium, gold sodium thiomalate, ketoprofen, auranofin, aurothioglucose,tolmetin sodium, and the like;

antigout agents (e.g., colchicine, allopurinol, and the like);

anticoagulants (e.g., heparin, heparin sodium, warfarin sodium, and thelike);

thrombolytic agents (e.g., urokinase, streptokinase, altoplase, and thelike);

antifibrinolytic agents (e.g., aminocaproic acid);

hemorheologic agents (e.g., pentoxifylline);

antiplatelet agents (e.g., aspirin, empirin, ascriptin, and the like);

anticonvulsants (e.g., valproic acid, divalproate sodium, phenytoin,phenytoin sodium, clonazepam, primidone, phenobarbitol, phenobarbitolsodium, carbamazepine, amobarbital sodiun, methsuximide, metharbital,mephobarbital, mephenytoin, phensuximide, paramethadione, ethotoin,phenacemide, secobarbitol sodium, clorazepate dipotassium,trimethadione, and the like);

agents useful for calcium regulation (e.g., calcitonin, parathyroidhormone, and the like);

antibacterial agents (e.g., amikacin sulfate, aztreonam,chloramphenicol, chloramphenicol palmitate, chloramphenicol sodiumsuccinate, ciprofloxacin hydrochloride, clindamycin hydrochloride,clindamycin palmitate, clindamycin phosphate, metronidazole,metronidazole hydrochloride, gentamicin sulfate, lincomycinhydrochloride, tobramycin sulfate, vancomycin hydrochloride, polymyxin Bsulfate, colistimethate sodium, colistin sulfate, and the like);

antifungal agents (e.g., griseofulvin, keloconazole, and the like);

antiviral agents (e.g., interferon gamma, zidovudine, amantadinehydrochloride, ribavirin, acyclovir, and the like);

antimicrobials (e.g., cephalosporins (e.g., cefazolin sodium,cephradine, cefaclor, cephapirin sodium, ceftizoxime sodium,cefoperazone sodium, cefotetan disodium, cefutoxime azotil, cefotaximesodium, cefadroxil monohydrate, ceftazidime, cephalexin, cephalothinsodium, cephalexin hydrochloride monohydrate, cefamandole nafate,cefoxitin sodium, cefonicid sodium, ceforanide, ceftriaxone sodium,ceftazidime, cefadroxil, cephradine, cefuroxime sodium, and the like),penicillins (e.g., ampicillin, amoxicillin, penicillin G benzathine,cyclacillin, ampicillin sodium, penicillin G potassium, penicillin Vpotassium, piperacillin sodium, oxacillin sodium, bacampicillinhydrochloride, cloxacillin sodium, ticarcillin disodium, azlocillinsodium, carbenicillin indanyl sodium, penicillin G potassium, penicillinG procaine, methicillin sodium, nafcillin sodium, and the like),erythromycins (e.g., erythromycin ethylsuccinate, erythromycin,erythromycin estolate, erythromycin lactobionate, erythromycin siearate,erythromycin ethylsuccinate, and the like), tetracyclines (e.g.,tetracycline hydrochloride, doxycycline hyclate, minocyclinehydrochloride, and the like), and the like);

antioxidants (e.g., N-acetylcsysteine, Vitamin A, Vitamin C, Vitamin E,β carotene, EUK-8, flavonoids, glutathione, α-lipoic acid, melatonin,retinols, and the like);

anti-infectives (e.g., miconazole, vidarabine, inosine, pranobex,vidarabine, inosine prabonex, cefpimizole sodium), fradiomycin, and thelike);

bronchodialators (e.g., sympathomimetics (e.g., epinephrinehydrochloride, metaproterenol sulfate, terbutaline sulfate, isoetharine,isoetharine mesylate, isoetharine hydrochloride, albuterol sulfate,albuterol, bitolterol, mesylate isoproterenol hydrochloride, terbutalinesulfate, epinephrine bitartrate, metaproterenol sulfate, epinephrine,epinephrine bitartrate), anticholinergic agents (e.g., ipratropiumbromide), xanthines (e.g., aminophylline, dyphylline, metaproterenolsulfate, aminophylline), mast cell stabilizers (e.g., cromolyn sodium),inhalant corticosteroids (e.g., flurisolidebeclomethasone dipropionate,beclomethasone dipropionate monohydrate), salbutamol, beclomethasonedipropionate (BDP), ipratropium bromide, budesonide, ketotifen,salmeterol, xinafoate, terbutaline sulfate, triamcinolone, theophylline,nedocromil sodium, metaproterenol sulfate, albuterol, flunisolide, andthe like);

hormones (e.g., androgens (e.g., danazol, testosterone cypionate,fluoxymesterone, ethyltostosterone, testosterone enanihate,methyltestosterone, fluoxymesterone, testosterone cypionate), estrogens(e.g., estradiol, estropipate, conjugated estrogens), progestins (e.g.,methoxyprogesterone acetate, norethindrone acetate), corticosteroids(e.g., triamcinolone, betamethasone, betamethasone sodium phosphate,dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate,prednisone, methylprednisolone acetate suspension, triamcinoloneacetonide, methylprednisolone, prednisolone sodium phosphatemethylprednisolone sodium succinate, hydrocortisone sodium succinate,methylprednisolone sodium succinate, triamcinolone hexacatonide,hydrocortisone, hydrocortisone cypionate, prednisolone, fluorocortisoneacetate, paramethasone acetate, prednisolone tebulate, predrisoloneacetate, prednisolone sodium phosphate, hydrocortisone sodium succinate,and the like), thyroid hormones (e.g., levothyroxine sodium) and thelike), and the like;

hypoglycemic agents (e.g., human insulin, purified beef insulin,purified pork insulin, glyburide, chlorpropamide, glipizide,tolbutamide, tolazamide, and the like);

hypolipidemic agents (e.g., clofibrate, dextrothyroxine sodium,probucol, lovastatin, niacin, and the like);

proteins (e.g., DNase, alginase, superoxide dismutase, lipase, and thelike);

nucleic acids (e.g., sense or anti-sense nucleic acids encoding anytherapeutically active protein, including the proteins described herein,and the like);

agents useful for erythropoiesis stimulation (e.g., erythropoietin);

antiulcer/antireflux agents (e.g., famotidine, cimetidine, ranitidinehydrochloride, and the like);

antinauseants/antiemetics (e.g., meclizine hydrochloride, nabilone,prochlorperazine, dimenhydrinate, promethazine hydrochloride,thiethylperazine, scopolamine, and the like);

septic shock agents, such as angiogenesis inhibitors (OLX-514),bradykinin antagonists (e.g., CP-0502, and NPC-17731), complement factorinhibitors (e.g., C3 convertase inhibitor), C5a release inhibitors(e.g., CAB-2.1), dopamine agonists (e.g., dopexamine), elastaseinhibitors (e.g., ONO-5046), E selectin antagonists (e.g., CY-1787),farnesyltransferase inhibitors (RBE limonene), immunostimulants (e.g.,CGP-19835A, lipid A vaccine, edobacomab, nebacumab, StaphGAM, anddiabodies), immunosuppressants (e.g., CytoTAB, and transcyclopentanylpurine analogues), interleukin 1 antagonists (e.g., interleukin 1receptors), interleukin 1 receptor antagonists (e.g., anakinra),interleukin 1b antagonists (e.g., interleukin-1β), interleukin 1betaconverting enzyme inhibitors (e.g., ICE-inhibitors), interleukin 8antagonists (e.g., IL-8 receptor), interleukin 13 agonists (e.g.,intereleukin-13), ITF-1697, lipase clearing factor inhibitors (e.g.,SC-59735), membrane permeability enhancers (e.g., BactericidalPermeability Increasing protein/BPI), nitric oxide antagonists (e.g.,hydroxocobalamin), nitric oxide synthase inhibitors (e.g., L-NMMA, andα-methyl-N-delta-iminoethyl-ornithine), P2 receptor stimulants (e.g.,ATP analogues), phosphatidic acid synthesis antagonists (e.g.,lisofylline), phospholipase A2 inhibitors (e.g., S-448,acylpyrrole-alkanoic acid derivatives, and indoleacetic acidderivatives), platelet activating factor antagonists (e.g., ABT-299,TCV-309, SM-12502,(2RS,4R)-3-(2-(3-pyridinyl)-thiazolidin-4-oyl)indoles, UR-12670, andE-5880), prostacyclin agonists (e.g., taprostene), prostaglandin E1agonists (e.g., TLC C-53), protein kinase inhibitors (e.g., SB-203580),protein kinase C inhibitors, protein synthesis antagonists (e.g.,procysteine), proteolytic enzyme inhibitors (e.g., nafamostat),SDZ-PMX-622, selectin antagonists (e.g., sulfated glycolipid celladhesion inhibitors), thrombin inhibitors (e.g., GS-522), TNFreceptor-Ig, tumor necrosis factor antagonists (e.g., anti-TNF MAbs,MAK-195F, TBP-I, Yeda, rhTNFbp, and CDP-571), tumor necrosis factoralpha antagonists (e.g., E-5531), and the like;

multiple sclerosis agents, such as 4-aminopyridine, 15±deoxyspergualin,ACTH, amantadine, antibody adjuvants (e.g., poly-ICLC, andpoly-IC+poly-L-lysine+carboxymethylcellulose), anti-cytokine MAb(CDP-835), anti-inflammatory (e.g., CY-1787, and CY-1503), anti-selectinMAb (e.g., CY-1787), anti-TCR MAb (e.g., NBI-114, NBI-115, and NBI-116),bacloten, bethanechol chloride, carbamazepine, carbohydrate drugs (e.g.,CY-1503), clonazepam, CNS and immune system function modulators (e.g.,NBI-106, and NBI-107), cyclophosphamide, cyclosporine A, cytokines(e.g., IFN-α, Ifaferone, IFN-β1b, betaseron, TGF-β2, PEG-TGF-β2,betakine, IFN-β/Rebif, frone, interferon-β, and IFN-β), CD4+T cellinhibitors (e.g., AnergiX), CD28 antagonists (e.g., B7-1, B7-2, andCD28), directcytotoxicity therapies (e.g., benzoporphyrin derivative(BPD)), FK-506, growth factors (e.g., glial growth factor, GGF, nervegrowth factors, TGF-β2, PEG-TGF-β2, and betakine), humanized MAb (e.g.,anti-IFN-γMAb, smart anti-IFN-γMAb, anti-Tac antibody, and smartanti-Tac antibody), humanized anti-CD4 MAb (e.g., anti-CD4 MAb,centara), hydrolase stimulants (e.g., castanospernine), IFN-α, IFN-γantagonist (e.g., anti-IFN-γMAb, and smart anti-IFN-γMAb), IL-2antagonists (e.g., tacrolimus, FK-506, FR-900506, Fujimycin, Prograf,IL-2 fusion toxin, and DAB₃₈₉IL-2), IL-4 antagonists (e.g., IL4 fusiontoxin, and DAB₃₈₉IL-4), immune-mediated neuronal damage inhibitors(e.g., NBI-114, NBI-115, and NBI-116), immunoglobins, immunostimulants(e.g., poly-ICLC, edelfosine, ALP, ET-18-OCH3, ET-18-OME, NSC-24, andpoly-IC+poly-L-lysine+carboxymethyl-cellulose), immunosuppressants(e.g., azathioprine, AI-100 animal protein, rDNA human protein AI-101,peptide, AI-102, castanospermine, tacrolimus, FK-506, FR-900506,Fujimycin, Prograf, anti-leukointegrin MAb, Hu23F2G, primatized anti-CD4antibody, CE9.1, Galaptin 14-1, GL14-1, Lectin-1, recombinant IML-1,linomide, roquinimex, LS-2616, transcyclo-pentanyl purine analogs,MS-6044, spanidin, 15-deoxyspergualin, deoxyspurgiline, gusperimus HCL,NSC-356894, NKT-01, TCR, CD3/Ti, cyclosporine, OL-27-400, SandImmune,Human IL-10, monogens, anti-TCR MAbs, TCAR MAbs, Monogen TM19, MonogenTM27, Monogen TM29, Monogen TM31, peptigen TP12, anti-CD4 MAb, cantara,immunophilins, VX-10367, VX-10393, VX-10428, synthetic basic copolymerof amino acids, copolymer-1, COP-1, T lymphocyte immunofusion (TIF)protein, and cyclophosphamide), integrin antagonists (e.g.,anti-integrin (cell adhesion molecule α4β1 integrin) MAbs, AN-100225,and AN-100226), interferon agonists (e.g., poly-ICLC, andpoly-ICtpoly-L-lysine+carboxymethyl-cellulose), interferon-β-1b,isoprinosine, IV methylprednisolone, macrolides (e.g., tacrolimus,FK-506, FR-900506, Fujimycin, and Prograf), MAO B inhibitors (e.g.,selegiline, and Parkinyl), methotrexate, mitoxantrone, muscle relaxants(e.g., RGH-5002), muscarinic antagonists (e.g., RGH-5002), neurosteroids(e.g., NBI-106, and NBI-107), octapeptides (e.g., peptide T), oxybutininchloride, oxygen free radical antagonists (e.g., tetrandrine,biobenzylisoquinoline alkaloid), peptide agonists (e.g., peptide T),phenoxybenzamine, phospholipase C inhibitors (e.g., edelfosine, ALP,ET-18-OCH3, ET-18-OME, NSC-24), photodynamic therapies (e.g.,benzoporphyrin derivative (BPD)), plasmapheresis, platelet activatingfactor antagonists (e.g., ginkgolide B, and BN-52021), potassium channelantagonists (e.g., aminodiaquine, and EL-970), propranolol,prostaglandin synthase inhibitors (e.g., sulfasalazine,salazosulfa-pyridine, PJ-306, SI-88, azulfidine, salazopyrin), proteaseantagonists (e.g., ginkgolide B, and BN-52021), recombinant soluble IL-1receptors, spergualin analogs (e.g., spanidin, 15-deoxyspergualin,deoxyspurgiline, gusperimus HCl, NSC-356894, NKT-01), TCR peptide decoys(e.g., NBI-114, NBI-115, and NBI-116), TCR peptidomimetic decoys (e.g.,NBI-114, NBI-115, and NBI-116), TCR peptide vaccines (e.g., AI-208(Vβ6.2/6.5 phenotype)), selectin antagonists (e.g., lectin-1, andrecombinant IML-1), soluble TNF receptor I, TCARs (e.g., TCR, CD3/Ti,and peptigen TP12), TNF antagonists (e.g., thalidomide, and TNFinhibitors), tricyclic antidepressants, and the like;

organ transplantation agents, such as anti-CD25 MAbs, anti-Tacantibodies, anti-TNF MAb (e.g., CDP571), apoptosin, azathioprines (e.g.,imuran), BCX-34, CA3, CD28, complement inhibiting factors (e.g., CD59),CTLA4Ig, cyclosporines (e.g., CsA), FK-506/rapamycin binding proteins(FKBP), glucocorticoids, humanized version of OKT3 (e.g., huOKT3-185),mycophenolate mofetil, hydroorotate dehydrogenase inhibitors (e.g.,Brequinar), orthoclone OKT3 (e.g., IgG2a anti-T cell murine monoclonalantibody, and muromonab-CD3), rapamycins (e.g., AY-22989), andstreptomyces isolates (e.g., FR-900520, and FR-900523), and the like;

systemic lupus erythematosus (SLE) agents, such as androgen-derivedsteriods (e.g., Org-4094), anti-CD4 humanized antibodies, anti-DNA/V-88,anti-idiotypic murine MAb (e.g., anti-idiotypic antibody to3E10/MAb1C7), CD2 antagonists (e.g., CD2), complement inhibitors (e.g.,recombinant MCP-based complement inhibitors), cyclosporines (e.g.,Sandimmune, cyclosporine analog, OG-37325, cyclosporin-G, and NVal-CyA),cytokines (e.g., IL-4 fusion toxin), cytokine receptor antagonists(e.g., immunomodulatory cytokines), E-selectin antagonists (e.g.,anti-ELAM, and CY-1787), FK506/tacrolimus (e.g., Prograf), hypercalcemicagents (e.g., KH-1060), IFN-γ antagonists (e.g., anti-IFN-γMAb, andsmart anti-IFN-γMAb), IL-1β converting enzyme inhibitors (ICE), IL-2produced by E. coli (e.g., celmoleukin, IL-2, TGP-3, and Celeuk),immunoglobulins (e.g., anti-ELAM, CY-1788, and humanized CY-1787),immunostimulants (e.g., thymotrinan, RGH-0205, and TP3),immunosuppressants (e.g., Rapamycin, AY-22989, NSC-226080, NSC-606698,anti-CD4, T-cell inhibitor, anti-tac MAb, smart anti-tac MAb, Migis(membrane immunoglobulin-isotope specific) antibodies, SM-8849,immunophilins, VX-10367, VX-10393, VX-10428, mycophenolate mofetil,ME-MPA, RS-61444, cyclosporine, OL-27-400, Sandimmune, IL-4 fusiontoxin, trypanosomal inhibitory factor (TIF), T-cell receptor, CD3/Ti,Org-4094, anti-TBM, CP 17193, Leflunomide/A-77-1726, ELAM-1, AnergiX,Spanidin, 15-deoxyspergualin, deoxyspurgiline, gusperimus hydrochloride,NSC-356894, NKT-01, Roquinimex, LS-2616, linomide, LJP-394, and CD-59antigen), immunotoxins (e.g., Zolimomab aritox, xmmly-h65-rta,xomazyme-lym/CD5-Plus, OrthoZyme-CD5+, XomaZyme-H65-rta, Xomazyme-CD5Plus), intravenous immunoglobulins (e.g., IVIG), integrin antagonists(e.g., integrin blockers), Migis antibodies, monoclonal antibodytherapeutics, murine MAb (e.g., anti-SLE vaccine, and MAb 3E10),primatized anti-CD4 antibodies (e.g., CE9.1), protease inhibitors (e.g.,matrix metalloprotease (MMP) inhibitors, and stromelysin), proteinsynthesis antagonists (e.g., anti-CD6-bR, anti-T12-bR, and oncolysinCD6), purine nucleoside phosphorylase inhibitors (e.g., BCX-25, andBCX-14), selectin antagonists (e.g., CY1503, and Cylexin), spergualinanalogues (e.g., Spanidin, 15-deoxyspergualin, deoxyspurgiline,gusperimus hydrochloride, NSC-356894, and NKT-01), T cell inhibitors(e.g., AnergiX), tumor necrosis factor (TNF) antagonists, and the like;

Alzheimer's disease agents, such as ACh release enhancers (e.g., T-588(benzothiophene derivative)), acetylcholine release stimulants (e.g.,DUP-996 and analogues), AMPA agonists (e.g., AMAlex, and Isoxazolecompound series), AMPA GluR agonist (e.g., IDRA-21[7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazinine]), AMPA GluRantagonists (e.g., S-18986, and related quinolone derivatives),anticholinesterases (e.g., E-2020), Ca-antagonists (e.g., NS-649, spidervenom-derived ICM peptides and analogues, and substituted 2-aminoindanescompound series), combined anticholinesterase and muscarinic AChRantagonists (e.g., PD142676), K-channel blockers (e.g.,Trans-R-4-(4-methoxyphenyl-methyl) cyclohexylanine and analogues, andmargatoxin-based functional and/or structural analogues), MI muscarinicreceptor agonists (e.g., Xanomeline), NMDA antagonists (e.g., certainindole derivatives, and(R-(R¹,S¹))-α-(4-hydroxyphenyl)-beta-methyl-4-(phenylmenthyl)-1-piperidinepropanoland analogues), nicotinic AChR agonists (e.g., ABT418 [isoxazole,3-meth-5-(1-meth-2-pyrrolidinyl)]), and the like;

antiparkinson agents (e.g., ethosuximide, and the like);

psoriasis agents, such as 5-LO inhibitors (e.g., Wy-50295, Wy49232,Lonapalene, RS43179, MK-886, L-663536, ETH-615, DUP-654, Zileuton,epocarbazolin-A, and A-64077), 5-LO/CO inhibitors (e.g., BF-397,Tenidap, CP-309, and CP-66248), angiogenesis inhibitors (e.g., plateletfactor 4), anticancer antibiotic (e.g., AGM-1470, and TNP470),anti-inflammatory cytochrome P450 oxidoreductase inhibitors (e.g.,DuP-630, and DuP-983), antiproliferative compounds (e.g., Zyn-Linker),arachidonic acid analogues (e.g., CD581, and CD554), arachidonic acidantagonists (e.g., Lonopalene, RS-43179, triamcinolone acetonide withpenetration enhancer Azone, betamethasone dipropionate steroid wipe,G-202, Halobetasol propionate, ultravate, Halometasone, C-48401-Ba, andSicorten), beta-glucan receptor antagonists, betamethasone steroidwipes, calcium metabolic moderators (e.g., Tacalcitol, Bonealfa, TV-02ointment, Ro-23-6474, KH-1060, Calcipotriol, BMS-181161, BMY-30434,Dovonex, and Divonex), CD4 binding inhibitors (e.g., PIC 060), celladhesion compounds (e.g., CY-726, VCAM-1, ELAM-1, and ICAM), celladhesion inhibitors (e.g., selectin inhibitor, GM-1930), cellular aginginhibitors (e.g., Factor X), corticosteroids (e.g., Halobetasolpropionate, ultravate, Halometasone, C-48401-Ba, and Sicorten),cyclosporin analogues (e.g., IMM-125), dihydrofolate reductaseinhibitors (e.g., G-301, dichlorobenzoprim, methotrexate, andmethotrexate in microsponge delivery system), E-selectin inhibitors(e.g., ISIS 4730), endogenous active form of vitamin D₃ (e.g.,Calcitriol, and Du-026325), fibroblast growth factor antagonists (e.g.,Saporin mitotoxin, and Steno-Stat), fumagillin analogues (e.g.,AGM-1470, and TNP-470), G-proteins and signal transduction compounds(e.g., CPC-A), gel formulations for acne (e.g., nicotinamide, N-547, andPapulex), growth hormone antagonists (e.g., Octreotide, Sandostatin,Lanreotide, angiopeptin, BIM-23014, and Somatuline), humanizedantibodies (e.g., anti-CD4 antibody), hydroorotate dehydrogenaseinhibitors (e.g., Brequinar sodium, bipenquinate, and DuP-785), ICAM-1inhibitors (e.g., ISIS 939), IL-1 and other cytokine inhibitors (e.g.,Septanil), IL-1 converting ezyme inhibitors, IL-1 receptor antagonists(e.g., Antril), IL-2 antagonists (e.g., Tacrolimus, Prograf, andFK-506), IL-2 receptor-targeted fusion toxins (DAB389IL-2), IL-8receptors, immunostimulants (e.g., Thymopentin, and Timunox),immunosuppressants (e.g., XomaZyme-CD5 Plus, cyclosporine, Sandimmune,SR-31747, anti-CD11, 18 MAb, Tacrolimus, Prograf, FK-506, and FK-507),immunosuppressive agents targeting FK506 (e.g., immunophilins, VX-10367,and VX-10428), immunotoxins MAb directed against CD antigen (e.g.,XomaZyme-CD5 Plus), leukotriene antagonists (e.g., Sch-40120, Wy-50295,and Wy-49232), leukotriene B4 antagonists (e.g., SC41930, SC-50605,SC-48928, ONO-4057, LB-457, LY-255283, LY-177455, LY-223982, LY-223980,and LY-255253), leukotriene synthesis inhibitors (MK-886, and L-663536),lipase clearing factor inhibitors (e.g., 1-docosanol, and lidakol),lipid encapsulated reducing agent (e.g., Dithranol), liposomal gel(e.g., Dithranol), LO inhibitors (e.g., CD581, CD554, Masoprocol, andActinex), lithium succinate ointments (e.g., lithium salts, andEfalith), LO/CO inhibitors (e.g., P-8892, P-8977, CHX-108, andFPL-62064), membrane integrity agonists (e.g., lithium salts, andEfalith), microtubule inhibitors (e.g., Posophyliotoxin-containingcompound, and Psorex), octapeptide somatostatin analogues (e.g.,Lanreotide, angiopeptin, BIM-23014, and Somatuline), oligonucleotides(e.g., ISIS 4730, ISIS 3801, ISIS 1939, and IL-1 inhibitors), peptideagonists (e.g., octapeptide, and peptide T), PKC inhibitors,phospholipase A2 compounds, pospholipase D compounds, photodynamicanticancer agents (e.g., 5-aminolevulinic acid, and 5-ALA), photodynamictherapies (e.g., benzoporphyrin derivative, synthetic chlorins,synthetic porphyrins, and EF-9), photosensitizer (e.g., Porfirmersodium), PKC inhibitors (e.g., Safmgol, and Kynac), platelet activatingfactor antagonists (e.g., TCV-309), platelet aggregation inhibitors(e.g., CPC-A), prodrug NSAIDs (e.g., G-201), prostaglandin agonist(e.g., eicosapentaenoic acid+gamma-linolenic acid combination, andEfamol Marine), protein inhibitors (e.g., SPC-103600, and SPC-101210),protein kinase C (PKC) inhibitors (e.g., Ro-31-7549, Ro-31-8161, andRo-31-8220), protein synthesis antagonists (e.g., Calcitriol, Du-026325,LG-1069, LG-1064, AGN-190168, Namirotene, and CBS-211A), purinenucleoside phosphorylase inhibitors (e.g., BCX-34), radical formationagonists (e.g., benzoporphyrin derivative), recombinantantileukoproteinases (e.g., ALP-242), retinoids (e.g., BMY-30123,LG-1069, and LG-1064), retinoid derivatives (e.g., AGN-190168),rapamycin binding proteins (FKBP) (e.g., immunophilins, VX-10367, andVX-10428), second generation monoaromatic retinoids (e.g., Acitretin,and Neotigason), soluble IL-1, IL-4 and IL-7 receptors, somatostatin andsomatostatin analogues (e.g., Octreotide, and Sandostatin), steroids,(e.g., AGN-191743), streptomyces anulatus isolates (e.g.,epocarbazolin-A), superoxide dismutase (e.g., EC-SOD-B), thymidylatesynthase inhibitors (e.g., AG-85, MPI-5002, 5-FU in biodegradablegel-like matrix, 5-FU and epinephrine in biodegradable gel-like matrix,and AccuSite), topical formulations (e.g., P-0751, and P-0802),transglutaminase inhibitors, tyrphostin EGF receptor kinase blockers(e.g., AG-18, and AG-555), VCAM-1 inhibitors (e.g., ISIS 3801), vitaminD analogues (e.g., Ro-23-6474, KH-1060, Calcipotriol, BMS-181161,BMY-30434, Dovonex, and Divonex), vitamin D₃ analogues (e.g.,Tacalcitol, Bonealfa, TV-02 ointment), and vitamin D₃ derivatives (e.g.,1,2-diOH-vitamin D₃), and the like;

diabetes agents, such as ACE inhibitors (e.g., captopril), amylin,amylin agonists and antagonists (e.g., Normylin™, AC137, GC747, AC253,and AC625), autoimmune compounds (e.g., AI-401), capsaicins (e.g.,Zostrix-HP), cell regulators (e.g., protein kinase C inhibitors, andBalanol), domperidones (e.g., Motilium®), fluvastatins (e.g., Lescol),FOX 988, fusion toxins (e.g., DAB₃₈₉IL-2, and DAB₄₈₆IL-2), genetherapies (e.g., Transkaryotic Therapies), glucagons (e.g., recombinantyeast glucagon), IL-10 compounds, iloprost, immunosuppressives (e.g.,tacrolimus, Prograf, and FK-506), proinsulin, insulin and insulinanalogs (e.g., AI-401, Nu-Insulin compounds, Humulin, Iletin, Humalog™,LYs-Pro, and Amaryl), insulin-like growth factors (e.g.,Chiron/Ciba-Geigy compounds, Fujisawa compounds, and Genetechcompounds), insulinotropins (e.g., Pfizer/Scios Nova compounds), nervegrowth factors (e.g., Genentech compounds), oral hypoglycemics (e.g.,AS-6, glimepiride, Amaryl, CL 316,243, acarbose, miglitol, recombinantyeast glucagon, GlucaGen™, NovoNorm™, glipizide, insulinotropin, andCI-991/CS-045), platelet-derived growth factors (e.g., ZymoGenetics/Novo Nordisk compounds), sulfonylureas (e.g., tolbutamide,acetohexamide, tolazamide, and chlorpropramide), T cell approaches(e.g., anergize, AnergiX™, Procept compounds, and T cell Sciencescompounds), and tolrestats (e.g., Alredase®, and ARI-509), activin,somatostatin, and the like;

stroke agents, such as 5-HT antagonists (e.g., Piperazine derivative),5-HT reuptake inhibitors (e.g., Milnacipran, and Dalcipran), 5-HT 1Aagonists (e.g., SR-57746A, and SR-57746), 5-HT 3 agonists (e.g.,SR-57227), 5-HT 4 antagonists, 5-lipoxygenase inhibitors (e.g., low MWdual 5-lipoxygenase and PAF inhibitor CMI-392), ACh agonists (e.g.,Pramiracetam, Choline-L- alfoscerate,L-alpha-glycerylphosphoryl-choline, and Delecit), adenosine agonists(e.g., GP-1-4683, ARA-100, and arasine analogs), adenosine A1 receptoragonists (e.g., Azaisotere, 2-chloro-N-[4 (phenylthio)-1-piperidinyl]adenosine, and 2120136), adenosine reuptake inhibitors (e.g.,Diphenyloxazole derivatives), adrenergic transmitter re-uptakeinhibitors (e.g., Bifemelane, E-0687, MCI-2016, Alnert, and Celeport),aldose reductase inhibitors (e.g., Spiro-3′ pyrroline derivatives),alpha antagonists (e.g., Drotaverine acephyllinate, and Depogen), alpha2 agonists (e.g., SNAP-5083, SNAP-5608, and SNAP-5682), AMPA receptoragonists (e.g., heterocyclic compound SYM-1207, and heterocycliccompound SYM-1252), AMPA receptor antagonists (e.g., LY-293558, andLY-215490), Ancrod/Arvin, aspirin, benzothiazoles (e.g., Lubeluzole, andR87926), benzodiazepine receptor antagonists (e.g.,3-oxadiazolyl-1,6-naph-thyridine derivatives, Tetracyclicimidazodiazepineseries imidazenil, FID-02-023, and Ro-23-1412), bloodsubstitutes, bradykinin antagonists (e.g., CP-0127, Bradycor, andSepticor), C5a release inhibitors (e.g., protein derivative CMI-46000),calcium antagonists (e.g., Lemildipine, NB-818, NPK-1886, Trimetazidinederivative, lomerizine KP-2796, Diltiazem analog clentiazem maleate, andTA-3090), calcium channel antagonists (e.g., nitrendipine-like compounddiperdipine, YS-201, U-92032, Diltiazem derivative, 1058, SM-6586,KP-840, F-0401, D-31-D, Tetrahydronaphthalene derivatives, fasudil,AT-877, H-7, HA-1044, HA-1077, Eril, darodipine, dazodipine, PY-108-068,Plimo, Dihydropy-ridine, AE 0047, GJ-0956, Lacidipine, GR-43659,GR-43659X, GX-1048, S-312-d, S-312, S-830312, Nilvadipine, and FK-235),calpain inhibitors (e.g., AK-275, and CX-275), carnitinepalmitoyl-transferase inhibitors, carvedilol, cerebral calciumantagonist vasodilators (e.g., Nimodipine, and Nimotop), cholinesteraseinhibitors (e.g., indole and indazole derivatives, and Tacrine analog),complement factor inhibitors (e.g., TK9C, protein derivative TP16,compinact A, compinact C, Factor D inhibitors, and soluble, recombinantMCP-based complement inhibitors), complement inhibitors (e.g.,sCRI/BRL-55730, and YM-203), coronary vasodilators (e.g., Nicorandil,RP-46417, SG-75, and Adancor), CPC-111, cytidyldiphosphocholine/citicholines, cytokines (e.g., NBI-117), Dexanabiol,dopamine agonists, EAA receptors, endothelin antagonists (e.g., SB209670), endothelin receptor antagonists, excitatory amino acid agonists(e.g., acylated polyamine analogs, andN-(4-hydroxyphenylpropa-nonyl)-spermine analog), excitatory amino acidantagonists (e.g., Tryptophan, 4,6-disubstituted stroke & kynureninederivatives, NPC-17742, CPC-701, and CPC-702), glutamate antagonists(e.g., Kainate quisqualate NNC-07-9202, NPC-17742, small moleculeCNS-1237, NS-257, NS-072, BW-619C, CGS 19755, Riluzole, PK-26124, and RP54274), glutamate receptor antagonists (e.g., Araxin compounds,Quinoxaline derivative, YM-90K, and YM-900), glycine antagonists,glycine NMDA agonists (e.g., 3-hydroxy-2,5-dioxo-1H-benz[b]azepines),glycine NMDA associated antagonists (e.g., 5,6-dihydro-1H-pyrrolo[1,2,3-de] quinoxaline-2,3-diones, Strychnine-insensitive glycinebinding site of NMDA receptor L-687414, Glystasins, ACEA-2011,ACEA-3031, AC-1021, ACPC, and eliprodil), growth factor antagonists(e.g., non-peptide indolocarbazole neutrophic molecules, and CEP-075),GPIIb/IIIa antagonists (e.g., Peptide C68-22), hemorheological agents(e.g., Drotaverine acephyllinate, and Depogen), heparin, hydroxylradical formation inhibitors (e.g., homopiperazine derivative K-7259),hypocalcemic agents (e.g., calcitonin peptide, related to hCGRPpeptide), hypothermic agents/BMY-20862, ICAM-1 compounds (e.g.,Enlimomab), immunosuppressants (e.g., small molecule compounds, andNBI-117), integrin general antagonists (e.g., monoclonal antibodyAN-100225, and monoclonal antibody AN-100226), Interleukin-1 antagonists(e.g., cyclic nitrones), iron-dependent lipid peroxidation inhibitors(e.g., 2-(amino-methyl) chromans), lactic acid accumulation/inhibitors(e.g., small molecule CPC-211), Leukotriene B4 antagonists (e.g.,Ebselen, DR-3305, PZ-25, PZ-51, RP 60931, and RP 61605), lipidperoxidase inhibitors (e.g., Idebenone, and Avan), low molecular weightsmall molecules, methyltransferase stimulants (e.g., 4-methylbenzenesulfonate, ademetionine sulfate tosilate, OF-156, and Ceritan),monoamine oxidase B inhibitors (e.g., MD-280040, MD-200243, MD-280080,Lazabemide, and Ro-19-6327), MS-153, MS-424,/Na⁺/H⁺Na⁺/Li⁺ exchangeinhibitors (e.g., Pyrazine derivatives), nadroparin (e.g., Fraxiparin),nafronyl/naftidrofuryl (e.g., Praxilene), nerve growth factor agonists(e.g., small molecule compounds, CNTF, BDNF, 2.5S NGF,monosialoganglioside GM1, and Sigen/Sygen), neuronal calcium channelblockers (e.g., CPC-304, and CPC-317), neuronal differentiationcompounds (e.g., F-spondin), neuropeptide agonists (e.g., NeurotrophicPeptide Trofexin), neutrophil inhibitory factors (e.g., small moleculecompounds), nitric oxide agonists (e.g., hydroxy derivative N-3393,hydroxy derivative N-3398, nicorandil, and Therapicon), nitric oxideantagonists, NMDA antagonists (e.g., Spiroisoindoles/dizocilpinederivatives, Oxindole compound, CP-112116, LY-104658, LY-235959,FR-115427, Sialic acid derivative, N-palmitoyl-Betaethylglycosideneuraminic acid, ND-37, Ro-01-6794, 706, Dextrorphan, Ifenprodilanalogue eliprodil, SL-82.0715, Lipophilic molecules, HU-211,Remacemide, 934-423, 12495, 12859, 12942AA, Selfotel, CGS-19755,SDZ-EAA494, CGP-40116, CGP-37849, CGP-39551, and CGP-43487), NMDAantagonist-partial agonists (e.g., Conantokin G peptide SYM-010), NMDAchannel blockers (e.g., Aptiganel, CERESTAT, and CNS 1102), NMDAreceptor antagonists, NMDA receptor subtypes (e.g., Kainate quisqua-lateNNC-07-9202), non-competitive NMDA antagonists (e.g., FPL-15896),non-ionic copolymer RheothRx, nootropic/acetylcholine agonists (e.g.,Oxiracetam, CT-848, and Neuractiv), norepinephrine inhibitors (e.g.,Midalci-pran), N-type calcium channel antagonists (e.g., NS-626, andNS-638), opioid antagonists (e.g., Nalmefene, nalmetrene, JF-1,ORF-11676, Cervene, and Incystene), opioid kappa receptor agonists(e.g., acrylacetamide enadoline, and CI-997), organoselenims (e.g.,Ebselen, DR-3305, PZ-25, PZ-51, RP 60931, and RP 61605), oxygenscavengers (e.g., Tirilazad mesylate, Lazaroids, and Freedox), PA2inhibitors (e.g., phospholipase A2 inhibitor), PAF antagonists (e.g.,nupafant, and BB-2113), partial glycine NMDA agonists (e.g., ACPC),peptide/GPIIb/IIIa antagonists (e.g., Integrelin), peptidicneuron-specific calcium channel antagonists (e.g., SNX-111),phosphodiesterase inhibitors (e.g., Xanthine derivatives,propentofylline, Hoe-285, and Hextol), phospholipase A2 inhibitors(e.g., small organic molecule CEP-217), plasminogen activators (e.g.,r-ProUK (recombinant pro-urokinase), platelet-activating factorantagonists (e.g., UK-74505), platelet adhesion inhibitors (e.g.,Peptide), platelet aggregation antagonists (e.g., cilostazol, peptideagents, GPHb-IIIA inhibitor, and TP-9201), platelet aggregationinhibitors (e.g., Diaminoalkanioic acid derivatives), potassium channelagonists (e.g., Nicorandil, RP-46417, SG-75, and Adancor), prolylendopeptidase (PEP) inhibitors (e.g., JTP-4819), protein kinase Cinhibitors (e.g., monosialoganglioside derivative Liga-20), proteolyticenzyme inhibitors (e.g., Protease nexin-1, Incyte, PN-1, PN-2,Nafamostat, FUT-175, Duthan, and Futhan), pyrimidine derivatives,Quinolizine derivatives (e.g., KF-17329, and KF-19863), radicalformation antagonists (e.g., EPC-K1), recombinant tissue plasminogenactivators (e.g., alteplase, and Activase), Schwann cell derivedmolecules/promoters, sigma antagonists (e.g., Sigma ligand), sigmareceptor antagonists (e.g., tetrahyropyridinyl-isoxazolines andisoxazoles PD-144418), sodium/calcium channel modulators (e.g.,Lifarizine, and RS-87476), sodium channel antagonists, streptokinase(e.g., Streptase), substituted guanadine (e.g., small moleculeCNS-1237), superoxide dismutase stimulants (e.g., PEG conjugated enzymesuperoxide dismutase/Dismutec, and PEG-SOD), thrombin inhibitors, (e.g.,non-peptide), thromboxane synthase inhibitors (e.g., Linotroban, andHN-11500), thyrotropin-releasing hormone agonists (e.g., TRH agonists,Protirelin analogthymoliberin, and RX-77368,), ticlopidine (e.g.,Ticlid), TJ-8007, TRH agonists (e.g., Thyrotropin releasing hormones,and JTP-2942), trilazard, urokinase (e.g., Abbokinase), w-conopeptide(e.g., SNX-111), and warfarin (e.g., Coumadin), and the like;

agents useful for the treatment of carcinomas (e.g., adriamycin, taxol,interleukin-1, interleukin-2 (especially useful for treatment of renalcarcinoma), and the like, as well as leuprolide acetate, LHRH analogs(such as nafarelin acetate), and the like, which are especially usefulfor the treatment of prostatic carcinoma),

agents useful for the treatment of endometriosis (e.g., LHRH analogs),

agents useful for the treatment of uterine contraction (e.g., oxytocin),

agents useful for the treatment of diuresis (e.g., vasopressin),

agents useful for the treatment of cystic fibrosis (e.g., Dnase (i.e.,deoxyribonuclease), SLPI, and the like),

agents useful for the treatment of neutropenia (e.g., GCSF),

agents useful for the treatment of lung cancer (e.g., beta1-interferon),

agents useful for the treatment of respiratory disorders (e.g.,superoxide dismutase),

agents useful for the treatment of ischemia/reperfusion injury (e.g.,selectin inhibitors, Irfl, and the like);

agents useful for the treatment of osteoporosis (e.g., statins, such aslovastatin, pravastatin, atorvastatin, and the like; bisphosphonates;and the like);

nitric oxide synthase inhibitors (e.g., N⁴-methyl-L-arginine,aminoguanidine, N⁴-(iminoethyl)-L-ornithine, thiocitrulline and othercitrulline derivatives, N⁴-nitro-L-arginine, N⁴-nitro-L-arginine methylester, N⁴-amino-L-arginine, and other arginine derivatives, isothioureaand its derivatives, and the like,

as well as a variety of other agents, such as acyclovir, alendronatesodium, amlodipine, ampicillin, azelaic acid, azithromycin,beclomethasone, betamethasone, bicalutamide, buspirone, carisoprodol,carvedilol, cefaclor, cefadroxil, cefixime, cefprozil, ceftibuten,cefuroxime axetil, cephalexin, cetirizine hydrochloride, cimetidine,ciprofloxacin, cisapride, clarithromycin, clavulanate, clonazepam,clotrimazole, codeine, conjugated estrogens, cyclobenzaprine,desogestrel, dexrazoxane, diazepam, dicyclomine HCl, digoxin, diltiazem,dirithromycin, doxazosin, doxycycline, enalapril, erythromycin,erythromycin base, erythromycin stearate, estradiol, ethinyl estradiol,ethynodiol diacetate, etodolac, famotidine, fluconazole, fluoxetine,fluvastatin, furosemide, gemfibrozil, glipizide, glyburide, guaifenesin,hydrochlorothiazide, hydrocodone, hydrocortisone, ibuprofen, ibutilidefumarate, indapamide, insulin, ipratropium bromide, ketoconazole,ketoprofen, ketorolac tromethamine, lamivudine, lansoprazole,levonorgestrel, levothyroxine, lisinopril, loracarbef, loratidine,lorazepam, losartan potassium, lovastatin, medroxyprogestrone,methylphenidate, methylprednisolone, metoprolol, metoprolol tartrate,moexipril hydrochloride, mometasone furoate, mupirocin, mycophenolatemofetil, nabumetone, nalmefene hydrochloride, naproxen, neomycin,nifedipine, nisoldipine, nitrofurantoin, nizatidine, norethindrone,norgestrel, nortriptyline, ofloxacin, omeprazole, oxaprozin, oxycodone,paroxetine, penicillin, pentoxifylline, phenylpropanolamine, phenytoin,polymyxin, porfimer sodium, potassium chloride, pravastatin, prednisone,promethazine, propoxyphene, pseudoephedrine, quinapril, ramipril,ranitidine, riluzole, salmeterol, saquinavir mesylate, sertraline,sevoflurane, simvastatin, sucralfate, sulfamethoxasole, sumatriptan,temazepam, terazosin, terconazole, terfenadine, tetracycline,theophylline, timolol, tramadol, tramadol hydrochloride, tretinoin,triamcinolone acetonide, triamterene, trimethoprim, valproic acid,venlafaxine, verapamil, wafarin, zolpidem, and the like.

The dithiocarbamate component and the pharmocalogically active agent ofinvention conjugates are indirectly covalently attached employing avariety of linkages (including a linker), e.g., ester linkages,disulfide linkages, amide linkages, ether linkages, thioether linkages,imide linkages, sulfate ester linkages, sulfonate ester linkages,phosphate ester linkages, carbonate linkages, O-glycosidic linkages,S-glycosidic linkages, and the like. Such linkages can be accomplishedusing standard synthetic techniques as are well known by those of skillin the art, either by direct reaction of the starting materials, or byincorporating a suitable functional group on the starting material,followed by coupling of the reactants.

Linker, L (also referred to herein as linker/spacer) contemplated foruse herein includes moieties having the structure —Y—W—,

wherein:

Y is alkylene, substituted alkylene, cycloalkylene, substitutedcycloalkylene, heterocyclic, substituted heterocyclic, oxyalkylene,substituted oxyalkylene, alkenylene, substituted alkenylene, arylene,substituted arylene, alkarylene, substituted alkarylene, aralkylene orsubstituted aralkylene, and

W=O, N, P or S.

Modifying groups contemplated for use in the practice of the presentinvention include:

—CR_(3,) —SiR_(3,)

—NR′_(2,) —PR′_(2,)

—OR″_(,) —SR″,

wherein:

each R is independently alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, alkylaryl, substitutedalkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substitutedarylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substitutedaroyl, acyl, substituted acyl, hydroxy, alkoxy, or substituted alkoxy;

each R′ is independently alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, alkylaryl, substitutedalkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substitutedarylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substitutedaroyl, acyl, substituted acyl, hydroxy, alkoxy, or substituted alkoxy;and

R″ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl,substituted arylalkyl, arylalkenyl, substituted arylalkenyl,arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl orsubstituted acyl.

In accordance with another embodiment of the present invention, thereare provided methods for the preparation of protected forms ofpharmacologically active agents, said method comprising covalentlyattaching a dithiocarbamate to said pharmacologically active agent. Theresulting conjugate provides a latent form of the pharmacologicallyactive agent, releasing the biological activity thereof only when thepharmacologically active component of said conjugate (including thelinker referred to above) is cleaved from said conjugate (e.g., by anesterase, amidase or other suitable enzyme).

As readily recognized by those of skill in the art, invention conjugatescan be prepared in a variety of ways. See, for example, Scheme 1,wherein a pharmacologically active compound (1) bearing a carboxylicmoiety can be reacted with a diol (2) under conditions suitable toproduce ester (3), which can then be activated by treatment with anarylsulfonyl chloride under conditions suitable to produce compound (5),which can then be coupled with the salt form of a dithiocarbamate (e.g.,compound 6B or disulfide thereof such as compound 6A) to produceinvention conjugate (7).

Employing this general reaction scheme, invention conjugates can beprepared from a wide variety of pharmacologically active agents. See,for example, Examples 6-13 provided herein.

In accordance with yet another embodiment of the present invention,there are provided methods for reducing the side effects induced byadministration of pharmacologically active agent(s) to a subject, saidmethod comprising covalently attaching a dithiocarbamate to saidpharmacologically active agent(s) prior to administration to saidsubject.

In accordance with still another embodiment of the present invention,there are provided methods for enhancing the effectiveness ofpharmacologically active agent(s), said method comprising covalentlyattaching a dithiocarbamate to said pharmacologically active agent.

In accordance with a still further embodiment of the present invention,there are provided improved methods for the administration ofpharmacologically active agent(s) to a subject for the treatment of apathological condition, the improvement comprising covalently attachinga dithiocarbamate to said pharmacologically active agent prior toadministration of said pharmacologically active agent to said subject.

Those of skill in the art recognize that the conjugates described hereincan be delivered in a variety of ways, such as, for example, orally,intravenously, subcutaneously, parenterally, rectally, by inhalation,and the like.

Depending on the mode of delivery employed, the conjugates contemplatedfor use herein can be delivered in a variety of pharmaceuticallyacceptable forms. For example, the conjugate can be delivered in theform of a solid, solution, emulsion, dispersion, micelle, liposome, andthe like.

Thus, in accordance with still another embodiment of the presentinvention, there are provided physiologically active composition(s)comprising invention conjugates in a suitable vehicle rendering saidconjugates amenable to oral delivery, transdermal delivery, intravenousdelivery, intramuscular delivery, topical delivery, nasal delivery, andthe like.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a micelle, aliposome, and the like, wherein the resulting composition contains oneor more of the compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. The activeingredient may be compounded, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfunes may be used. The activecompound(s) (e.g., one or more pharmacologically active agents,covalently bound to a dithiocarbamate of structure I) is(are) includedin the pharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or disease condition.

Pharmaceutical compositions containing the active ingredient may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874, to form osmotictherapeutic tablets for controlled release.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, for example,peanut oil, liquid paraffin, or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Conjugates contemplated for use in the practice of the present inventionmay also be administered in the form of suppositories for rectaladministration of the drug. These compositions may be prepared by mixingthe drug with a suitable non-irritating excipient, such as cocoa butter,synthetic glyceride esters of polyethylene glycols, which are solid atordinary temperatures, but liquify and/or dissolve in the rectal cavityto release the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

In general, the dosage of invention conjugate employed as describedherein falls in the range of about 0.01 mmoles/kg body weight of thesubject/hour up to about 0.5 mmoles/kg/hr. Typical daily doses, ingeneral, lie within the range of from about 10 g up to about 100 mg perkg body weight, and, preferably within the range of from 50 g to 10 mgper kg body weight and can be administered up to four times daily. Thedaily IV dose lies within the range of from about 1 g to about 100 mgper kg body weight, and, preferably, within the range of from 10 g to 10mg per kg body weight.

In accordance with yet another embodiment of the present invention,there are provided improved methods for the treatment of a subjectsuffering from a pathological condition by administration thereto ofpharmacologically active agent(s), the improvement comprising covalentlyattaching a dithiocarbamate to said pharmacologically active agent priorto administration thereof to said subject.

Thus, invention method for the treatment of a subject afflicted with apathological condition comprises administering to a subject an effectiveamount of a modified pharmacologically active agent,

wherein said pharmacologically active agent is effective for treatmentof said condition, and

wherein said pharmacologically active agent has been modified by thecovalent attachment thereto of a dithiocarbamate.

The invention will now be described in greater detail by reference tothe following non-limiting examples.

EXAMPLE 1 Preparation of an Ester Conjugate of Pyrrolidinol andIbuprofen

To 200 ml of methylene chloride in a 500-ml reaction vessel was added 24grams of ibuprofen (α-methyl-4-(2-methylpropyl)benzene-acetic acid), 10grams of 2-pyrrolidinol and 0.5 grams of a suitable coupling agent,e.g., dicyclohexylcarbodiimide. The reaction proceeds at roomtemperature for 1 to 3 hours with stirring. The ester conjugate isisolated and purified with a 60-70% yield.

EXAMPLE 2 Conversion of an Ester Conjugate of Pyrrolidinol and Ibuprofento an Ester Conjugate of Pyrrolidinol Dithiocarbamate and Ibuprofen

To 100 ml of methanol in a 500-ml reaction vessel was added 10 grams ofthe ester conjugate obtained from Example 1. An aqueous NaOH solution(6.9 grams in 10 ml water) is added dropwise to the reaction mixture at4° C. The reaction is allowed to proceed for one additional hour at 4°C. A solution mixture of carbon disulfide (5 ml) and ethanol (15 ml) isadded dropwise to the above reaction mixture with slow stirring at 4° C.The final product is isolated and purified with a yield of about 70%.

EXAMPLE 3 Preparation of an Ester Conjugate of L-proline and Adriamycin

To 200 ml of methylene chloride in a 500-ml reaction vessel was added47.2 grams of adriamycin, 10 grams of L-proline and 0.5 grams of anysuitable coupling agent, e.g., dicyclohexylcarbodiimide. The reaction isallowed to proceed at room temperature for 1 to 3 hours with stirring.The ester conjugate is isolated and purified with about 70% yield.

EXAMPLE 4 Conversion of an Ester Conjugate of L-proline and Adriamycinto an Ester Conjugate of L-proline Dithiocarbamate and Adriamycin

To 100 ml of methanol in a 500-ml reaction vessel was added 10 grams ofthe ester conjugate obtained from Example 3. An aqueous NaOH solution(6.9 grams in 10 ml) water is added dropwise to the reaction mixture at4° C. The reaction is allowed to proceed for one additional hour at 4°C. A solution mixture of carbon disulfide (5 ml) and ethanol (15 ml) isadded dropwise to the above reaction mixture with slow stirring at 4° C.The final product is isolated and purified with a yield of about 70%.

EXAMPLE 5 General Procedure for the Preparation of Invention Conjugates

5A. General procedure for the preparation of intermediate 3 (Scheme 1).To a stirring solution of pharmacologically active compound (1) (1 eq),diol compound (2) (5 eq) and dimethylaminopyridine (DMAP) (0.2 eq) inanhydrous THF is added 1,3-dicyclohexylcarbodiimide (DCC) (1 eq) at 0°C. The resulting solution is stirred at room temperature for severalhours. The reaction solution is filtered and the solvent is evaporated.The residue is partially dissolved in ethyl acetate and the solid isfiltered off and the solution is washed with 0.5 N HCl, saturated sodiumbicarbonate solution and brine. After the solvent is evaporated, thecompound is purified either by flash chromatography or recrystallizationto give compound 3.

5B. General procedure for the preparation of intermediate 4 (Scheme 1).To a solution of compound 3 (1 eq) in pyridine is addedp-toluenesulfonylchloride (4) (2 eq) at 0° C. The resulting solution is put in therefrigerator (˜4° C.) for three days. The reaction solution is pouredonto ice and extracted with ether. The combined ether solution is washedwith water and dried. After the solvent is evaporated, the residue ispurified by appropriate means to give compound 5.

5C. General procedure for the preparation of conjugate compound 7(Scheme 1). A solution of intermediate 5 and compound 6A or 6B in DMSOis stirred at room temperature under argon for one to three hours. Thereaction solution is poured onto ice and extracted with ether. Thecombined ether solution is washed with water. The ether is dried andevaporated and the residue is purified by appropriate means to give theconjugate compound 7.

EXAMPLE 6 Synthesis of Invention Conjugate of Naproxen

The synthetic steps described in this example are illustrated in Scheme2:

6A. 3-Hydroxypropyl (S)-(+)-methoxy-α-methyl-2-naphthaleneacetate 10(Scheme 2). To a stirring solution of(S)-(+)-methoxy-α-methyl-2-naphthaleneacetic acid (naproxen, 8) (10.4 g,45 mmol), propanediol (9) (17.1 g, 225 mmol) and DMAP (0.54 g, 4.5 mmol)in anhydrous THF (300 mL) is added DCC (9.4 g, 45 mmol) at 0° C. Theresulting solution is stirred at 0° C. for 10 min and then at roomtemperature for 5 h. The reaction solution is filtered and the solventis evaporated. The residue is partially dissolved in ethyl acetate andthe solid is filtered off and the solution is washed with 0.5 N HCl,saturated sodium bicarbonate solution and brine. The organic phase isdried (Na₂SO₄) and the solvent is evaporated. The residue is purified byrecrystallization from 1:3 hexanes-dichloromethane to give 9.7 g (75%)of compound 10 as a white solid; ¹H NMR (CDCl₃) 1.58 (d, 3H), 1.78 (m,2H), 1.88 (t, 1H, ex D₂O), 3.53 (m, 2H), 3.87 (q, 1H), 3.90 (s, 3H), 4.2(m, 2H), 7.11-7.15 (m, 2H), 7.39 (d, 1H), 7.65 (s, 1H), 7.70 (d, 2H); MS(ES) m/z 289.2 (M+H)⁺ (C₁₇H₂₂O₄ requires 289.34).

6B. 3-Tosylpropyl (S)-(+)-methoxy-methyl-2-naphthaleneacetate 11 (Scheme2). To a stirring solution of compound 10 (8.6 g, 30 mmol) in 35 mL ofpyridine is added tosyl chloride (4) (11.43 g, 60 mmol) at 0° C. Theresulting solution is put in the refrigerator (˜4° C.) for three days.The reaction solution is poured onto 300 g ice and extracted with ether.The combined ether solution is washed with 10% HCl solution, saturatedNaHCO₃ solution and brine. The solution is dried (Na₂SO₄) andevaporated. The residue is purified by flash chromatography on a silicagel column using 100% CH₂Cl₂ as the eluent to give 8.92 g (67%) ofcompound 11 as a pale yellow oil; ¹H NMR (CDCl₃) 1.53 (d, 3H), 1.90 (m,2H), 2.42 (s, 3H), 3.78 (q, 1H), 3.91 (s, 3H), 3.99 (m, 1H), 4.09 (t,2H), 7.11-7.15 (m, 2H), 7.25-7.28 (m, 2H), 7.32-7.34 (m, 1H), 7.64 (m,1H), 7.65-7.71 (m, 4H); MS (ES) m/z 443.3 (M+H)⁺ (C₂₄H₂₇O₆S requires443.53).

6C. Compound 12 from Compound 6A (Scheme 2). To a stirring solution ofcompound 11 (8.86 g, 20.02 mmol) in 35 mL of DMSO is added compound 6A(3.86 g, 9.1 mmol) at room temperature. The resulting solution isstirred at room temperature for 70 min. The reaction solution is pouredonto 100 g ice and extracted with ether. The combined ether solution iswashed with water and brine. The solution is dried (Na₂SO₄) andevaporated. The residue is purified by flash chromatography on a silicagel column using 200:1 and then 20:1 CH₂Cl₂—CH₃OH as eluents to give3.74g (45%) of compound 12 as a white foam; ¹H NMR (CDCl₃) 1.57 (d, 6H),1.94-2.20 (m, 12H), 3.20-3.25 (m, 4H), 3.57-3.59 (m, 2H), 3.72-3.79 (m,2H), 3.84-3.88 (m, 2H), 3.90 (s, 6H), 5.05 (m, 2H), 7.10-7.14 (m, 4H),7.39-7.41 (d, 2H), 7.65-7.70 (m, 6H); MS (ES) m/z 921.5 M⁺(C₄₆H₅₂N₂O₁₀S₄ requires 921.2).

6D. Compound 12 from Compound 6B (Scheme 2). To a stirring solution ofcompound 5 (2.21 g, 5mmol) in 10 mL of anhydrous DMSO is added compound6B (1.06, 4.5 mmol) at room temperature. The resulting solution isstirred at room temperature for 80 min. The reaction solution is pouredinto water and washed with ether. The aqueous solution is acidified topH=3-4 using concentrated HCl solution and extracted withdichloromethane. The combined organic phase is washed with water andbrine. The organic phase is dried over Na₂SO₄ and the solvent isevaporated under high vacuum to give 1.3g (63%) of the compound 12.Compound 12 from this procedure has the same ¹H NMR and MS spectra withthe compound from the above procedure using compound 6A.

EXAMPLE 7 Alternate Synthetic Methods for Preparation of a Series ofConjugates of Naproxen

The naproxen derivatives described in this example are illustrated inScheme 3.

7A. Compound 18 (Scheme 3). To a stirring solution of compound 11 (8.84g, 20.0 mmol) in 35 mL of DMSO was added compound 13 (2.28 g, 20 mmol)at rt. The resulting solution was stirred at rt for 2.5 h. The reactionsolution was poured on to 100 g ice and extracted with ether. Thecombined ether solution was washed with water and brine. The solutionwas dried (Na₂SO₄) and evaporated. The residue was purified to give70-80% yield of compound 18.

7B. Compound 19 (Scheme 3). Compound 19 was prepared as described abovefor compound 18 from compound 11 (8.84 g, 20.0 mmol) in 35 mL of DMSOand compound 14 (2.56 g, 20 mmol). The reaction gave 70-80% yield ofcompound 19.

7C. Compound 20 (Scheme 3). Compound 20 was prepared as described abovefor compound 18 from compound 11 (8.84 g, 20.0 mmol) in 35 mL of DMSOand compound 15 (3.52 g, 20 mmol). The reaction gave 70-80% yield ofcompound 20.

7D. Compound 21 (Scheme 3). Compound 21 was prepared as described abovefor compound 18 from compound 11 (8.84 g, 20.0 mmol) in 35 mL of DMSOand compound 16 (3.84 g, 20 mmol). The reaction gave 70-80% yield ofcompound 21.

7E. Compound 22. Compound 22 was prepared as described above forcompound 18 from compound 11 (8.84 g, 20.0 mmol) in 35 mL of DMSO andcompound 17 (3.32 g, 20 mmol). The reaction gave 70-80% yield ofcompound 22.

EXAMPLE 8 Additional Synthetic Methods for Preparation of Conjugates ofNaproxen

The naproxin derivatives described in this example are illustrated inScheme 4.

8A. Compound 25 (Scheme 4). Compound 25 was prepared as described abovefor compound 18 from compound 11 (8.84 g, 20.0 mmol) in 35 mL of DMSOand compound 23 (2.88 g, 20 mmol). The reaction gave 70-80% yield ofcompound 25.

8B. Compound 26 (Scheme 4). Compound 26 was prepared as described abovefor compound 18 from compound 11 (8.84 g, 20.0 mmol) in 35 mL of DMSOand compound 24 (3.20 g, 20 mmol). The reaction gave 70-80% yield ofcompound 26.

EXAMPLE 9 Synthesis of Invention Conjugate of Ibuprofen

The synthetic steps described in this example are illustrated in Scheme5:

9A. 3-Hydroxypropyl (S)-(+)-4-isobutyl-α-methylphenylacetate 28 (Scheme5). Compound 28 is prepared as described above for compound 10 from(S)-(+)-4-isobutyl-α-methylphenylacetic acid (ibuprofen, 27) (4.12g, 20mmol) and propanediol (7.6 g, 100 mmol). The compound is purified byflash chromatography on a silica gel column using 10:1 and then 3:1hexanes-ethyl acetate as eluents to give 3.54 g (65%) of compound 28 asa colorless oil; ¹H NMR (CDCl₃) 0.89 (d, 6H), 1.49 (d, 3H), 1.80 (m,2H), 1.76-1.85 (m, 2H, 1H ex D₂O), 2.45 (m, 2H), 3.52 (m, 2H), 3.70 (q,1H), 4.21 (m, 2H), 7.10 (d, 2H), 7.18 (d, 2H); MS (ES) m/z 265.7(M+H)⁺(C₁₆H₂₅O₃ requires 265.36).

9B. 3-Tosylpropyl (S)-(+)-4-isobutyl-α-methylphenylacetate 29 (Scheme5). Compound 29 is prepared as described above for compound 11 fromcompound 28 (1.76 g, 0.56 mmol) and tosyl chloride (4) (0.5 g, 1.13mmol). The compound is purified by flash chromatography on a silica gelcolumn using CH₂Cl₂ as the eluent to give 1.5 g (54%) of the compound 29as a colorless oil; ¹H NMR (CDCl₃) δ 0.88 (d, 6H), 1.43 (d, 3H),1.80-1.92 (m, 3H), 2.44 (d, 2H), 2.45 (s, 3H), 3.61 (q, 1H), 3.99 (t,2H), 4.08 (t, 2H), 7.07 (d, 2H), 7.13 (d, 2H), 7.33 (d, 2H), 7.75 (d,2H); MS (ES) m/z 441.3 (M+Na)⁺ (C₂₃H₃₀O₅SNa requires 441.55).

9C. Compound 30 (Scheme 5). Compound 30 is prepared as described abovefor compound 12 from compound 29 (1.35 g, 3.2 mmol) and compound 6A (0.7g, 1.6 mmol) or 6B (0.75 g, 3.3 mmol) in DMSO. The compound is purifiedby flash chromatography on a silica gel column using 200:1 and then 20:1CH₂Cl₂—CH₃OH as eluents to give 0.55 g (40%) of compound 30 as a paleyellow oil; ¹H NMR (CDCl₃) δ 0.89 (d, 6H), 1.49 (d, 3H), 1.84 (m, 1H),2.00 (m, 2H), 2.17-2.32 (m, 4H), 2.44 (d, 2H), 3.23 (m, 2H), 3.71 (m,2H), 3.81 (m, 1H), 7.08 (d, 2H), 7.24 (d, 2H), MS (ES) m/z 873.2 M⁺(C₄₄H₆₀N₂O₈S₄ requires 873.22).

EXAMPLE 10 Synthesis of Invention Conjugate of Ketoprofen

The synthetic steps described in this example are illustrated in Scheme6:

10A. 3-Hyroxypropyl (S)-(+)-3-benzoyl-α-methylbenzeneacetate 32 (Scheme6). Compound 32 is synthesized as described above for compound 10 from(S)-(+)-3-benzoyl-α-methylbenzeneacetic acid (ketoprofen, 31) (3.8 g, 15mmol) and propanediol (9) (5.7 g, 75 mmol). The compound is purified byflash chromatography on a silica gel column using 200:1 CH₂Cl₂—MeOH asthe eluent to give 2.63 g (56%) of the compound 32 as a colorless oil;¹H NMR (CDCl₃) 61.54 (d, 3H), 1.82 (m, 2H), 1.82-1.82 (b, 1H, ex D₂O),3.58 (m, 2H), 3.79-3.83 (q, 1H), 4.25 (m, 2H), 7.42-7.80 (m, 9H); MS(ES) m/z 313.1 (M+H)⁺ (C₁₉H₂₁O₄ requires 313.3).

10B. 3-Tosylpropyl (S)-(+)-3-benzoyl-α-methylbenzeneacetate 33 (Scheme6). Compound 33 is synthesized as described above for compound 11 fromcompound 32 (2.48 g, 7.94 mmol) and compound 4 (3.03 g, 15.9 mmol). Thecompound is purified by flash chromatography on a silica gel columnusing 6:1 and then 4:1 hexanes-ethyl acetate as eluents to give 2.72 g(74%) of the compound 33 as a colorless oil; ¹H NMR (CDCl₃) δ 81.49 (d,3H), 1.94 (m, 2H), 2.43 (s, 3H), 3.73 (q, 1H), 4.01 (t, 2H), 4.11 (t,2H), 7.31-7.79 (m, 13H); MS (ES) m/z 467.3 (M+H)⁺ (C₂₆H₂₇O₆S requires467.55).

10C. Compound 34 (Scheme 6). Compound 34 is prepared as described abovefor compound 12 from compound 6A (0.91 g, 2.15 mmol) or 6B (1.01g, 4.3mmol) and compound 33 (2.0 g, 4.30 mmol) in 9 ml of DMSO. The compoundis purified by flash chromatography on a silica gel column using 3:1hexanes-ethyl acetate and then 20:1 CH₂Cl₂—MeOH as eluents to give 1.21g (58%) of the compound 34 as a pale yellow oil; ¹H NMR (CDCl₃) δ 1.44(d, 3H), 1.82-2.11 (m, 6H), 3.12-3.28 (m, 2H), 3.59-3.72 (m, 2H),3.61-3.75 (m, 2H), 3.90-4.15 (m, 3H), 4.85 (m, 1H), 7.51-7.73 (m, 9H);MS (ES) m/z 969.5 (M+H)⁺ (C₅₀H₅₃N₂O₁₀S₄ requires 969.22).

EXAMPLE 11 Alternate Synthetic Methods for Preparation of a Series ofConjugates of Ketoprofen

The ketoprofen derivatives described in this example are illustrated inScheme 7.

11A. Compound 40 (Scheme 7). Compound 40 was prepared as described abovefor compound 18 from compound 33 (9.32 g, 20.0 mmol) in 35 mL of DMSOand compound 35 (2.28 g, 20 mmol). The reaction gave 70-80% yield ofcompound 40.

11B. Compound 41 (Scheme 7). Compound 41 was prepared as described abovefor compound 18 from compound 33 (9.32 g, 20.0 mmol) in 35 mL of DMSOand compound 36 (2.56 g, 20 mmol). The reaction gave 70-80% yield ofcompound 41.

11C. Compound 42 (Scheme 7). Compound 42 was prepared as described abovefor compound 18 from compound 33 (9.32 g, 20.0 mmol) in 35 mL of DMSOand compound 37 (3.52 g, 20 mmol). The reaction gave 70-80% yield ofcompound 42.

11D. Compound 43 (Scheme 7). Compound 43 was prepared as described abovefor compound 18 from compound 33 (9.32 g, 20.0 mmol) in 35 mL of DMSOand compound 38 (3.84 g, 20 mmol). The reaction gave 70-80% yield ofcompound 43.

11E. Compound 44 (Scheme 7). Compound 44 was prepared as described abovefor compound 18 from compound 33 (9.32 g, 20.0 mmol) in 35 mL of DMSOand compound 39 (3.32 g, 20 mmol). The reaction gave 70-80% yield ofcompound 44.

EXAMPLE 12 Additional Synthesis of Ketoprofen Conjugates

The ketoprofen derivatives described in this example are illustrated inScheme 8.

12A. Compound 47 (Scheme 8). Compound 47 was prepared as described abovefor compound 18 from compound 33 (9.32 g, 20.0 mmol) in 35 mL of DMSOand compound 45 (2.88 g, 20 mmol). The reaction gave 70-80% yield ofcompound 47.

12B. Compound 48 (Scheme 8). Compound 48 was prepared as described abovefor compound 18 from compound 33 (9.32 g, 20.0 mmol) in 35 mL of DMSOand compound 46 (3.20 g, 20 mmol). The reaction gave 70-80% yield ofcompound 48.

EXAMPLE 13 Synthesis of Invention Conjugate of Indomethacin

The systhetic steps described in this example are illustrated in Scheme9:

13A. 3-Hydroxypropyl1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate 50 (Scheme 9).Compound 50 is prepared as described above for compound 10 from1-(-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid (indomethacin,49) (1.8 g, 5.0 mmol) and propanediol (9) (1.9 g, 25 mmol). The compoundis purified by flash chromatography on a silica gel column using 200: 1,100:1 and 50:1 CH₂Cl₂—MeOH as eluents to give 1.02 g (49%) of thecompound 50 as a pale yellow oil; ¹H NMR (CDCl₃) δ 1.70 (t, 1H, ex D₂O),1.86 (m, 2H), 2.39 (s, 3H), 3.63 (q, 2H), 3.68 (s, 2H), 3.84 (s, 3H),4.27 (t, 2H), 6.67 (d, 1H), 6.86 (d, 1H), 6.95 (d, 1H), 7.48 (d, 2H),7.66 (d, 2H); MS (ES) m/z 416.5 (M+H)⁺ (C₂₂H₂₃ClNO₅ requires 416.87).

13B. 3-Tosylpropyl 1-p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate51 (Scheme 9). Compound 51 is prepared as described above for compound11 from compound 50 (0.96 g, 2.3 mmol) and compound 9 (0.88 g, 4.6mmol). The compound is purified by flash chromatography on a silica gelcolumn using 3:1 hexanes-ethyl acetate as the eluent to give 0.93 g(71%) of the compound 51 as a pale yellow oil; ¹H NMR (CDCl₃) δ 1.98 (m,2H), 3.62 (s, 2H), 3.82 (s, 3H), 4.05 (t, 2H), 4.14 (t, 2H), 6.67 (d,1H), 6.90 (d, 1H), 6.93 (d, 1H), 7.32 (d, 2H), 7.47 (d, 2H), 7.66 (d,2H), 7.74 (d, 2H); MS (ES) m/z 592.0 (M+Na)⁺ (C₂₉H₂₈ClNO₇SNa requires592.13).

13C. Compound 52 (Scheme 9). Compound 52 was prepared as described abovefor compound 12 from compound 51 (0.89 g, 1.56 mmol) and compound 6A(0.33 g, 0.78 mmol) or 6B (0.37g, 1.56 mmol). The compound is purifiedby flash chromatography on a silica gel column using 200:1 and then 20:1CH₂Cl₂—MeOH as eluents to give 0.33 g (36%) of the compound 52 as awhite foam; ¹H NMR (CDCl₃) δ 2.01-2.30 (m, 6H), 2.38 (s, 3H), 3.29 (t,2H), 3.68 (m, 4H), 3.84 (s, 3H), 4.19 (t, 2H), 5.13 (t, 1H), 6.66 (m,1H), 6.87 (d, 1H), 6.96 (d, 1H), 7.46 (d, 2H), 7.66 (d, 2H); MS (ES) m/z1177.5 (M+H)⁺ (C₅₄H₅₃Cl₂N₄O₂S₄ requires 1177.2).

EXAMPLE 14 Enzymatic Hydrolysis of Invention Conjugates

14A. Enzymatic hydrolysis of compound 12. Compound 12 (4.6 mg, 0.0049mmol) was dissolved in 0.25 ml of DMSO to make a 0.02M solution. Theabove solution (0.05 mL) was transferred to 1 mL of PBS buffer and mixedwith 33.3 units of the esterase. The resulting solution was put in awater bath (37° C.) for 30 min and then at rt overnight. The compoundwas decomposed into two compounds; Silica gel TLC R_(f) 0.46 (naproxen)and R_(f) 0.12 (20:1 CH₂Cl₂—MeOH).

14B. Enzymatic hydrolysis of compound 30. Compound 30 was hydrolyzed asdescribed above for compound 12. The compound 30 was decomposed into twocompounds within 5 h; Silica gel TLC R_(f) 0.64 (ibuprofen) and R_(f)0.12 (20:1 CH₂Cl₂—MeOH).

14C. Enzymatic hydrolysis of compound 34. Compound 34 was hydrolyzed asdescribed above for compound 12. The compound 34 was decomposed into twocompounds within 5 h; Silica gel TLC R_(f) 0.45 (ketoprofen) and R_(f)0.12 (20:1 CH₂Cl₂—MeOH).

14D. Enzymatic hydrolysis of compound 52. Compound 52 was hydrolyzed asdescribed above for compound 12. The compound 52 was decomposed into twocompounds within 5 h; Silica gel TLC R_(f) 0.44 (indomethacin) and R_(f)0.12 (20:1 CH₂Cl₂—MeOH).

EXAMPLE 15 Evaluation of the Effects of the Conjugate of PyrrolidinolDithiocarbamate and Ibuprofen (PDI) on the Acute Gastric Mucosal Injury

Wistar rats (200-250 grams, male) are fasted overnight but allowed freeaccess to water. Ten rats in each group are given ibuprofen or PDIorally at doses of 10, 20 or 50 mg/kg. The rats are sacrificed fivehours later and visible gastric damage is assessed by examining undermicroscope and histological evaluation.

EXAMPLE 16 Evaluation of the Effects of the Conjugate of PyrrolidinolDithiocarbamate and Ibuprofen (PDI) on Chronic Gastric Ulcer

White New Zealand rabbits (male, about 1 kg) are given subcutaneouslyibuprofen or PDI at a dose of 30 mg/kg for every 12 hours. The animalsare sacrificed on day 4 (after the 7th dose) and the visible ulcers inthe stomach are examined and measured with calipers. The tissue samplesare fixed in neutral buffered formalin and processed for histologicalevaluation.

EXAMPLE 17 Evaluation on the Anti-inflammatory Effects of the Conjugateof Pyrrolidinol Dithiocarbamate and Ibuprofen (PDI)

Wistar rats (male, 200-250 g) are fasted overnight but allowed to freeaccess to drinking water. Ibuprofen or PDI is given orally at a dose of1, 10, or 30 mg/kg (6 animals each group). After one hour, the rats areanesthetized and 0.1 ml of lambda carrageenan (0.1% solution) isinjected into the right hind foot pad. The volume of the pad is measuredby hydroplethysmometry every hour for the next five hours.

EXAMPLE 18 Evaluation of the Effects of the Conjugate of PyrrolidinolDithiocarbamate and Ibuprofen (PDI) on Prostaglandin Synthesis

Wistar rats (male, 200-250 g) are fasted overnight but allowed freeaccess to drinking water. The rats are anesthetized and their backs areshaved. After an incision to the back, a sponge (2.5×1×0.5 cm) soakedwith 2 ml of 0.5% carrageenan is implanted. Five hours later, the rats(6 animals in each group) are given orally either ibuprofen or PDI at adose of 30 mg/kg or vehicle control. One hour later, the rat issacrificed and the sponge is carefully removed. The exudate is recoveredfrom the sponge and the prostaglandin E2 level in the exudate ismeasured by enzyme-linked immunosorbent assay.

EXAMPLE 19 Evaluation on the Protective Effects of the Conjugate ofL-proline Dithiocarbamate and Adriamycin (PDA) AgainstAdriamycin-induced Cardiotoxicity

Balb/c mice (male, 20-25 g) are fed a standard diet and allowed freeaccess to drinking water. The mice are anesthetized and the telemetrysystem consisting of implantable transmitters, a telemetry receiver andanalog ECG adapter is implanted in the peritoneal cavity of each mouse.After surgery, the mice are allowed to recover for two weeks. The miceare given intravenously either adriamycin or PDA at a dose of 4 mg/kgthrough the tail vein. The treated mice are observed for two weeks. Thebody wight, ECG and heart rate are recorded daily. At the end of thestudy, the animals are sacrificed and the hearts are processed forhistological evaluation.

EXAMPLE 20 Reduced Numbers of Gastric Erosions in the Rat GastropathyModel by Naproxen-derived Conjugate of the Invention

The main side effect of NSAIDs is gastrointestinal ulceration andintolerance. Gastric damage from orally dosed NSAIDs has both localerosive and systemic ulcerative components. The ability to cause localerosions can be estimated by using the rat gastropathy model (Brand, S Jet al. supra). Sprague-Dawley rats (male, 175-250 g), were food fastedovernight and then dosed orally with 5 to 10 ml/kg of drug, followed byremoval of drinking water. After 2.5 hours, the rats were injected i.v.with Evans Blue to stain the gastric erosions. Thirty minutes later theanimals were sacrificed by CO₂ inhalation and the stomachs removed,opened along the greater curvature, and washed with water. The totalnumber of blue lesions was counted and the length of the lesions noted.

Administration of Naproxen at 15 and 30 mg/kg and equimolar doses ofNaproxen—containing conjugate of the invention (27 & 54 mg/kg) resultedin a dose-related number of lesions for both compounds (FIG. 1). Most ofthe lesions were linear or oval in shape and less than 2 mm in length;they were found primarily in the corpus of the stomach. The groupsubjected to high dose of the Naproxen—containing conjugate of theinvention had significantly fewer lesions than the high dose naproxengroup (ANOVA; p<0.005). The group subjected to low doseNaproxen—containing conjugate of the invention also showed fewererosions than the low dose of naproxen, but statistical significance wasnot achieved with only 6 animals in each group. These results suggestthat the naproxen prodrug, i.e., Naproxen—containing conjugate of theinvention, has the ability to reduce the number of erosions in thecorpus of the stomach after oral administration in the rat.

EXAMPLE 21 Reduction of Acute Hindlimb Inflammation in the RatCarrageenan-induced Hindlimb Edema Model by Naproxen ContainingConjugates of the Invention

Efficacy of NSAIDs in acute inflammation can be estimated by usingintraplantar injection of carrageenan in the rat. Male Sprague-Dawleyrats (200-250 g) were injected intradermally in the footpad with 50 μlof a 1% carrageenan solution in PBS. Swelling of the injected paw wasmeasured at 2, 3, 5 & 7 hours using a plethysmometer.

Pretreatment with oral naproxen given one hour before the carrageenaninjection at 10 mg/kg resulted in a significant reduction in swellingthat lasted from 2 to 5 hours post injection (FIG. 2). An equimolar doseof Naproxen—containing conjugate of the invention (18 mg/kg) reducedinflammation significantly at 2 and 3 hours, but started to wear off by5 hours. These results suggest that Naproxen—containing conjugate of theinvention is orally active in rats, but slightly less effective vs acuteinflammation than the parent drug.

Conclusions: Oral Naproxen—containing conjugates according to theinvention have antiinflammatory activity similar to naproxen in thechronic adjuvant arthritis and acute carrageenan hindlimb edema ratmodels. The tendency to cause gastric erosions is reduced inNaproxen—containing conjugates according to the invention. Thus,Naproxen—containing conjugates according to the invention may beeffective prodrug form of naproxen with reduced gastric side effects.

EXAMPLE 22 Reduction of Chronic Hindlimb Inflammation in the RatAdjuvant Arthritis Model by Naproxen—containing Conjugates of theInvention

NSAIDs are useful in both chronic and acute inflammatory conditions.Efficacy in chronic inflammation can be estimated using the rat adjuvantarthritis model (Blackham et al. supra). In this model Lewis male rats(175-250 g) were injected intradermally in the footpad with M.tuberculosis powder suspended in mineral oil at 5 mg/ml. Progressiveswelling of the uninjected paw and ankle joint between days 11 and 15was measured by plethysmometry.

Rats were dosed daily by by oral gavage with 5 ml/kg of naproxen at 1and 10 mg/kg and equimolar doses of Naproxen—containing conjugate of theinvention (1.8 and 18 mg/kg) on days 5-8 and 11-14. The high doses ofboth drugs produced a comparable reduction of swelling on days 13through 15 (FIG. 3), with a reduction compared to control ofapproximately 70% by day 15. The lower doses also appeared to have aslight effect by day 15. The results show that equimolar doses ofNaproxen—containing conjugate of the invention resulted inantiinflammatory effects equal to those of naproxen in this model.

EXAMPLE 23 Pharmacokinetics of Naproxen in Plasma Following IntravenousAdministration of Naproxen in Rats or Naproxen—containing Conjugates ofthe Invention

Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) that is widelyused in the treatment of rheumatoid arthritis, osteoarthritis, juvenilearthritis, ankylosing spondylitis, tendinitis and bursitis, and acutegout. Naproxen sodium, the sodium salt of naproxen, has also beendeveloped as an analgesic because it is more rapidly absorbed. The sideeffects of GI ulceration, bleeding, and perforation is problematic tonaproxen and NSAID therapy in general. Therefore, any therapeuticapproach that decreases the side effects of naproxen could widen theusage of this therapy in treating inflammatory diseases.

The test articles utilized were Naproxen—containing conjugates of theinvention (Medinox, Inc., San Diego) stored as a powder (at 4° C.) andnaproxen (Sigma, St. Louis) stored at room temperature. On the day ofanimal dosing, test articles were freshly prepared in the mixture ofcarboxymethylcellulose (Sigma, St. Louis) and dimethylsulfoxide (Sigma,St. Louis) or water for injection.

Rats were catheterized using the carotid artery and jugular vein. Thecatheters were flushed with 30% polyvinylpyrrolidone (400 U/mL ofheparin) to prevent clotting in the tip. 250 μL blood samples werecollected by unhooking the flush syringe and letting the blood flowfreely into centrifuge tubes at predetermined time points (see Table 1).The tubes were centrifuged at 13,000 rpm for 10 min at 4° C. All plasmasamples were analyzed for naproxen content on the same day ofcollection. A 50 μL aliquot of plasma sample was mixed with 100 μL ofacetonitrile. After vortexing and centrifugation, 100 μL of supernatantwas collected and added to 150 μL of 50 mM phosphate buffer (pH 5.0).After vortexing and centrifugation, 25 μL of supernatant was analyzedfor naproxen by HPLC using a UV detector.

Pharmacokinetic analysis: The average plasma concentration at each timepoint was calculated and utilized in a pharmacokinetic analysis.Compartmental or noncompartmental pharmacokinetic analyses wereperformed using the WinNonlin program to calculate the followingparameters: maximum concentration at 2 minutes (C_(max)), time tomaximum concentration (T_(max)), area under the curve from zero to thelast time point (AUC_(last)), area under the curve from zero to infinitetime (AUC_(inf)), terminal phase half life (Beta-t_(½)), total plasmaclearance (CL), and volume distribution at steady state (V_(ss)).

TABLE 1 Rat group assignment and doses Test Dose Article Group # Rat #(mg/kg) Plasma Sample Time Naproxen 2 1, 2, 3, & 4 IV 5 min, 0.5, 1, 2,3, 4, (0.55 mg/kg) 5, 6, 7, & 8 hrs Naproxen 1 1, 2, 3, & 4 IV 5 min,0.5, 1, 2, 3, 4, prodrug (1 mg/kg) 5, 6, 7, & 8 hrs Note that 1 mg ofNaproxen prodrug contains 0.55 mg of naproxen.

FIG. 4 presents the naproxen plasma concentration-time curves. After IVadministration of naproxen, the naproxen plasma concentrations declinedwith bi-exponential manner (blackened rectangles), while the decline ofNaproxen prodrug was monophasic (opened triangles). Table 2 shows thenaproxen pharmacokinetic parameters. Both sets of pharmacokineticparameters were similar except (5.39 and 1.98 μg/mL for naproxen andNaproxen prodrug administration, respectively). This slow release ofnaproxen from Naproxen prodrug might be advantageous in helping toreduce naproxen's side effects by slowing the rise of plasma C_(max). Inaddition, the results show clearly that when administered intravenously,naproxen is released from Naproxen prodrug and appears in thecirculation.

TABLE 2 Naproxen plasma pharmacokinetic parameters (n = 4, pooled data)after IV administration of Naproxen prodrug or naproxen in rats(compartmental analysis) Amount C_(max) AUC_(all) AUC_(inf) t_(½) CLV_(ss) Drug (mg/kg) (μg/mL (μg * min/mL (hrs) (mL/hr * kg) (L/kg)Naproxen 0.55 5.39 N/A 14.60 4.36 38 0.22 Naproxen 1.00 1.98 N/A 12.704.44 43 0.28 prodrug

EXAMPLE 24 Plasma Pharmacokinetics of Naproxen Following OralAdministration of Naproxen Prodrug or Naproxen in Rats

The cannulated rats were separated into two groups as shown in Table 3.After oral gavage, the blood samples were withdrawn in various timepoints (Table 3) for HPLC analysis of naproxen levels.

TABLE 3 Rat group assignment and doses Test Dose Article Group # Rat #(mg/kg) Plasma Sample Time Naproxen 2 5, 6, 7, & 8 oral 0.25, 0.5, 1, 3,5, 7, 9, (2.2 mg/kg) 11, 13 & 14 hrs Naproxen 1 1, 2, 3, & 4 oral 0.25,0.5, 1, 3, 5, 7, 9, prodrug (4 mg/kg) 11, 13 & 14 hrs Note that 4 mg ofthe Naproxen prodrug contains 2.2 mg of naproxen.

FIG. 5 presents the naproxen plasma concentration-time curves (afteroral administration of naproxin (open triangles) and naproxen prodrug(blackened rectangles). Following oral administration of Naproxenprodrug, the time to maximum naproxen plasma levels was considerablydelayed compared to naproxen (T_(max) of 1.3 and 6.4 hours for Naproxenprodrug and naproxen, respectively) (Table 4). The corresponding C_(max)values were 2.34 and 4.05 aμg/mL, respectively. There was no significantdifference for AUC_(inf) values. The lower C_(max), longer T_(max), andsimilar AUC_(inf) of Naproxen prodrug could be significant factors inreducing the side effects of naproxen.

TABLE 4 Naproxen plasma pharmacokinetic parameters (n = 4, pooled data)after oral administration of Naproxen prodrug or naproxen in rats(compartmental analysis) Dose C_(max) T_(max) AUC_(all) AUC_(inf) t_(½)Drug (mg/kg) (μg/mL) (hrs) (μg * hr/mL) (hrs) Naproxen 2.2 4.82 1.3 N/A48.4 6.0 Naproxen 4   2.34 6.4 N/A 45.6 7.5 prodrug

Based on plasma data, Naproxen prodrug by oral or IV administration,produces better naproxen pharmacokinetic profiles than naproxen itself.

While the invention has been described in detail with reference tocertain preferred embodiments thereof, it will be understood thatmodifications and variations are within the spirit and scope of thatwhich is described and claimed.

That which is claimed is:
 1. A chemically modified pharmacologicallyactive agent having the structure: Z—C(S)—S—L—Q wherein: Q=apharmacologically active agent, L=a linker/spacer, and Z=a modifyinggroup, wherein the pharmacologically active agent is aspirin,α-methyl-4-(2-methylpropyl)benzene acetic acid (ibuprofen),2-(3-benzoylphenyl)propionic acid (ketaprofen),d-2-(6-methoxy-2-naphthyl)propionic acid (naproxen),2-((2,6-dichlorophenyl)amino)benzene acetic acid (diclofenac),adriamycin, cyciosporin,17-allyl-1,14-dihydroxy-12-(2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl)-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-(22,3.1.0)octacos-18-ene-2,3,10,16-tetraone(FK506), LFA-1, selectin inhibitors, tissue plasminogen activator or(S)-4-(2-benzothiazolyl)methylamino-α-(3,4-difluorophenoxy)methyl-1-pipieridineethanol(lubeluzole).
 2. A chemically modified pharmacologically active agentaccording to claim 1 wherein the linkage between said pharmacologicallyactive agent and the —S—C(S)— moiety is selected from the groupconsisting of ester linkages, disulfide linkages, amide linkages, etherlinkages, thioether linkages, imide linkages, sulfate ester linkages,sulfonate ester linkages, phosphate ester linkages, carbonate linkages,β-glycosidic linkages and S— glycosidic linkages.
 3. A chemicallymodified pharmacologically active agent according to claim 2 whereinsaid linkage is an ester linkage.
 4. A chemically modifiedpharmacologically active agent according to claim 1 wherein saidmodifying group is: —CR₃, —SiR₃, —NR′₂, —PR′₂, —OR, —SR″, wherein: eachR is independently alkyl, substituted alklyl, cycloalkyl, substitutedcycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl,arylalkynyl, substituted arylalkyl, arylalkenyl, substitutedarylalkenyl, arylarkynyl, substituted arylalalkynyl, aroyl, substitutedaroyl, acyl, substituted acyl, hydroxy, alkoxy, or substituted alkoxy;and each R′ is independently alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, alkylaryl, substitutedalkylaryl, arylalkyl substituted arylalkyl, arylalkenyl, substitutedarylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substitutedaroyl, acyl, substituted acyl, hydroxy, alkoxy, or substituted alkoxy;and R″ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl,substituted arylalkyl, arylalkenyl, substituted arylalkenyl,arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl,substituted acyl.
 5. A composition comprising the chemically modifiedpharmacologically active agent according to claim 1 in apharmaceutically acceptable carrier therefor.
 6. The compositionaccording to claim 5, wherein said pharmaceutically acceptable carrieris selected from a solid, solution, emulsion, dispersion, micelle orliposome.
 7. The composition according to claim 5 further comprising anenteric coating.